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1.  Additive Interactions Between Susceptibility Single-Nucleotide Polymorphisms Identified in Genome-Wide Association Studies and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium 
Joshi, Amit D. | Lindström, Sara | Hüsing, Anika | Barrdahl, Myrto | VanderWeele, Tyler J. | Campa, Daniele | Canzian, Federico | Gaudet, Mia M. | Figueroa, Jonine D. | Baglietto, Laura | Berg, Christine D. | Buring, Julie E. | Chanock, Stephen J. | Chirlaque, María-Dolores | Diver, W. Ryan | Dossus, Laure | Giles, Graham G. | Haiman, Christopher A. | Hankinson, Susan E. | Henderson, Brian E. | Hoover, Robert N. | Hunter, David J. | Isaacs, Claudine | Kaaks, Rudolf | Kolonel, Laurence N. | Krogh, Vittorio | Le Marchand, Loic | Lee, I-Min | Lund, Eiliv | McCarty, Catherine A. | Overvad, Kim | Peeters, Petra H. | Riboli, Elio | Schumacher, Fredrick | Severi, Gianluca | Stram, Daniel O. | Sund, Malin | Thun, Michael J. | Travis, Ruth C. | Trichopoulos, Dimitrios | Willett, Walter C. | Zhang, Shumin | Ziegler, Regina G. | Kraft, Peter | Joshi, Amit D. | Lindström, Sara | Hunter, David J. | Kraft, Peter | Hüsing, Anika | Barrdahl, Myrto | Kaaks, Rudolf | Kraft, Peter | VanderWeele, Tyler J. | Trichopoulos, Dimitrios | Campa, Daniele | VanderWeele, Tyler J. | Campa, Daniele | Canzian, Federico | Gaudet, Mia M. | Figueroa, Jonine D. | Chanock, Stephen J. | Hoover, Robert N. | Ziegler, Regina G. | Baglietto, Laura | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Giles, Graham G. | Severi, Gianluca | Berg, Christine D. | Buring, Julie E. | Lee, I-Min | Zhang, Shumin | Chirlaque, María-Dolores | Chirlaque, María-Dolores | Diver, W. Ryan | Thun, Michael J. | Dossus, Laure | Dossus, Laure | Giles, Graham G. | Haiman, Christopher A. | Schumacher, Fredrick | Stram, Daniel O. | Henderson, Brian E. | Hankinson, Susan E. | Isaacs, Claudine | Kolonel, Laurence N. | Krogh, Vittorio | Marchand, Loic Le | Lund, Eiliv | McCarty, Catherine A. | Overvad, Kim | Peeters, Petra H. | Peeters, Petra H. | Riboli, Elio | Sund, Malin | Travis, Ruth C. | Trichopoulos, Dimitrios | Trichopoulos, Dimitrios | Willett, Walter C.
American Journal of Epidemiology  2014;180(10):1018-1027.
Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 × 10−5) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)2). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.
PMCID: PMC4224360  PMID: 25255808
additive interactions; breast cancer; genome-wide association studies; single-nucleotide polymorphisms
2.  Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models  
The Journal of Clinical Investigation  2009;119(11):3395-3407.
Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94 (7.5%) primary human RMS tumors. The mutants K535 and E550 increased autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3 cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell lines expressing the empty vector or wild-type FGFR4. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe to be the first known mutations in a receptor tyrosine kinase in RMS. These findings support the potential therapeutic targeting of FGFR4 in RMS.
PMCID: PMC2769177  PMID: 19809159
3.  CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk 
British Journal of Cancer  2016;114(2):221-229.
Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene–environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.
We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen–progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case–control logistic regression as primary tests. The Cocktail test was used as secondary test.
The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52–0.72), P=4.8 × 10−9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52–0.78), P=1.2 × 10−5 (alpha threshold=3.1 × 10−4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61–1.50); A/C, 0.61 (0.39–0.95) and A/A, 0.40 (0.22–0.73), respectively.
Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.
PMCID: PMC4815813  PMID: 26766742
GWAS; colorectal cancer; menopausal hormone therapy; polymorphisms; gene–environment interaction; cytochrome P450
4.  Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis 
Carcinogenesis  2015;37(1):87-95.
In this genome-wide association study of colorectal cancer outcomes, multiple novel variants in the 6p12.1 region were identified as significantly associated with survival among individuals with distant-metastatic colorectal cancer.
Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2–8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10−8 in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10−10 and HR = 1.8, P = 3.7×10−9 for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.
PMCID: PMC4715234  PMID: 26586795
5.  PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS 
Southey, Melissa C | Goldgar, David E | Winqvist, Robert | Pylkäs, Katri | Couch, Fergus | Tischkowitz, Marc | Foulkes, William D | Dennis, Joe | Michailidou, Kyriaki | van Rensburg, Elizabeth J | Heikkinen, Tuomas | Nevanlinna, Heli | Hopper, John L | Dörk, Thilo | Claes, Kathleen BM | Reis-Filho, Jorge | Teo, Zhi Ling | Radice, Paolo | Catucci, Irene | Peterlongo, Paolo | Tsimiklis, Helen | Odefrey, Fabrice A | Dowty, James G | Schmidt, Marjanka K | Broeks, Annegien | Hogervorst, Frans B | Verhoef, Senno | Carpenter, Jane | Clarke, Christine | Scott, Rodney J | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Yang, Rongxi | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Bojesen, Stig | Nielsen, Sune F | Flyger, Henrik | Benitez, Javier | Zamora, M Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan | Ziogas, Argyrios | Clarke, Christina A | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V | Antonenkova, Natalia N | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Spurdle, Amanda B | Wauters, Els | Smeets, Dominiek | Beuselinck, Benoit | Floris, Giuseppe | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Olson, Janet E | Vachon, Celine | Pankratz, Vernon S | McLean, Catriona | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Kristensen, Vessela | Alnæs, Grethe Grenaker | Zheng, Wei | Hunter, David J | Lindstrom, Sara | Hankinson, Susan E | Kraft, Peter | Andrulis, Irene | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Jukkola-Vuorinen, Arja | Grip, Mervi | Kauppila, Saila | Devilee, Peter | Tollenaar, Robert A E M | Seynaeve, Caroline | Hollestelle, Antoinette | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Eccles, Diana M | Rafiq, Sajjad | Tapper, William J | Gerty, Sue M | Hooning, Maartje J | Martens, John W M | Collée, J Margriet | Tilanus-Linthorst, Madeleine | Hall, Per | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Cox, Angela | Reed, Malcolm W R | Luccarini, Craig | Baynes, Caroline | Dunning, Alison M | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Simard, Jacques | Dumont, Martine | Soucy, Penny | Eeles, Rosalind | Muir, Kenneth | Wiklund, Fredrik | Gronberg, Henrik | Schleutker, Johanna | Nordestgaard, Børge G | Weischer, Maren | Travis, Ruth C | Neal, David | Donovan, Jenny L | Hamdy, Freddie C | Khaw, Kay-Tee | Stanford, Janet L | Blot, William J | Thibodeau, Stephen | Schaid, Daniel J | Kelley, Joseph L | Maier, Christiane | Kibel, Adam S | Cybulski, Cezary | Cannon-Albright, Lisa | Butterbach, Katja | Park, Jong | Kaneva, Radka | Batra, Jyotsna | Teixeira, Manuel R | Kote-Jarai, Zsofia | Al Olama, Ali Amin | Benlloch, Sara | Renner, Stefan P | Hartmann, Arndt | Hein, Alexander | Ruebner, Matthias | Lambrechts, Diether | Van Nieuwenhuysen, Els | Vergote, Ignace | Lambretchs, Sandrina | Doherty, Jennifer A | Rossing, Mary Anne | Nickels, Stefan | Eilber, Ursula | Wang-Gohrke, Shan | Odunsi, Kunle | Sucheston-Campbell, Lara E | Friel, Grace | Lurie, Galina | Killeen, Jeffrey L | Wilkens, Lynne R | Goodman, Marc T | Runnebaum, Ingo | Hillemanns, Peter A | Pelttari, Liisa M | Butzow, Ralf | Modugno, Francesmary | Edwards, Robert P | Ness, Roberta B | Moysich, Kirsten B | du Bois, Andreas | Heitz, Florian | Harter, Philipp | Kommoss, Stefan | Karlan, Beth Y | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjaer, Susanne Krüger | Høgdall, Estrid | Peissel, Bernard | Bonanni, Bernardo | Bernard, Loris | Goode, Ellen L | Fridley, Brooke L | Vierkant, Robert A | Cunningham, Julie M | Larson, Melissa C | Fogarty, Zachary C | Kalli, Kimberly R | Liang, Dong | Lu, Karen H | Hildebrandt, Michelle A T | Wu, Xifeng | Levine, Douglas A | Dao, Fanny | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S | Marks, Jeffrey R | Akushevich, Lucy | Cramer, Daniel W | Schildkraut, Joellen | Terry, Kathryn L | Poole, Elizabeth M | Stampfer, Meir | Tworoger, Shelley S | Bandera, Elisa V | Orlow, Irene | Olson, Sara H | Bjorge, Line | Salvesen, Helga B | van Altena, Anne M | Aben, Katja K H | Kiemeney, Lambertus A | Massuger, Leon F A G | Pejovic, Tanja | Bean, Yukie | Brooks-Wilson, Angela | Kelemen, Linda E | Cook, Linda S | Le, Nhu D | Górski, Bohdan | Gronwald, Jacek | Menkiszak, Janusz | Høgdall, Claus K | Lundvall, Lene | Nedergaard, Lotte | Engelholm, Svend Aage | Dicks, Ed | Tyrer, Jonathan | Campbell, Ian | McNeish, Iain | Paul, James | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S | Rothstein, Joseph H | McGuire, Valerie | Sieh, Weiva | Cai, Hui | Shu, Xiao-Ou | Teten, Rachel T | Sutphen, Rebecca | McLaughlin, John R | Narod, Steven A | Phelan, Catherine M | Monteiro, Alvaro N | Fenstermacher, David | Lin, Hui-Yi | Permuth, Jennifer B | Sellers, Thomas A | Chen, Y Ann | Tsai, Ya-Yu | Chen, Zhihua | Gentry-Maharaj, Aleksandra | Gayther, Simon A | Ramus, Susan J | Menon, Usha | Wu, Anna H | Pearce, Celeste L | Van Den Berg, David | Pike, Malcolm C | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Moes-Sosnowska, Joanna | Kupryjanczyk, Jolanta | Pharoah, Paul DP | Song, Honglin | Winship, Ingrid | Chenevix-Trench, Georgia | Giles, Graham G | Tavtigian, Sean V | Easton, Doug F | Milne, Roger L
Journal of medical genetics  2016;53(12):800-811.
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
PMCID: PMC5200636  PMID: 27595995
6.  Mosaic loss of chromosome Y is associated with common variation near TCL1A 
Nature genetics  2016;48(5):563-568.
Mosaic loss of the Y chromosome (mLOY) leading to gonosomal XY/XO commonly occurs during aging, particularly in smokers. We investigated whether mLOY was associated with non-hematologic cancer in three prospective cohorts (8,679 cancer cases and 5,110 cancer-free controls), and genetic susceptibility to mLOY. Overall, mLOY was observed in 7% of men and increased with age (per year OR=1.13, 95%CI=1.12–1.15; P<2×10−16), reaching 18.7% among men over age 80. mLOY was associated with current smoking (OR=2.35, 95%CI=1.82–3.03; P=5.55×10−11); however, the association weakened with years after cessation. mLOY was not consistently associated with overall or specific cancer risk (e.g. for bladder, lung, or prostate) nor with cancer survival after diagnosis (multivariate-adjusted hazard ratio=0.87, 95% CI=0.73–1.04, P=0.12). In a genome-wide association study, we observed the first example of a common susceptibility locus for genetic mosaicism, specifically mLOY, which maps to the T-cell leukemia/lymphoma 1A (TCL1A) gene on 14q32.13, marked by rs2887399 (OR=1.55, 95%CI=1.36–1.78; P=1.37×10−10).
PMCID: PMC4848121  PMID: 27064253
7.  Evolution of multiple cell clones over a 29-year period of a CLL patient 
Nature Communications  2016;7:13765.
Chronic lymphocytic leukaemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. We identify chromosome alterations 13q14−, 6q− and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy.
Studying the genetic progression of many cancers is difficult as longitudinal samples are rarely available. Here, the authors analyse a patient with chronic lymphocytic leukaemia over a 29 year period and track the clonal evolution of the patient's disease and response to therapy.
PMCID: PMC5171825  PMID: 27982015
8.  Association of Breast Cancer Risk loci with Breast Cancer Survival 
The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS (HRper-allele=0.70; 95% CI: 0.58–0.85; Ptrend=2.84×10−4; HRheterozygotes=0.71; 95% CI: 0.55–0.92; HRhomozygotes=0.48; 95% CI: 0.31–0.76; P2DF=1.45×10−3). In silico, the C allele of LSP1-rs3817198 was predicted to increase expression of the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C). In the meta-analysis, TNRC9-rs3803662 was significantly associated with increased death hazard (HRMETA =1.09; 95% CI: 1.04–1.15; Ptrend=6.6×10−4; HRheterozygotes=0.96 95% CI: 0.90–1.03; HRhomozygotes= 1.21; 95% CI: 1.09–1.35; P2DF=1.25×10−4). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1-rs3817198 and TNRC9-rs3803662.
PMCID: PMC4615576  PMID: 25611573
breast cancer; SNP; survival; BPC3; meta-analysis
9.  Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study 
PLoS Medicine  2016;13(12):e1002162.
Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.
Methods and Findings
We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10−50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. Our study’s limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.
These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.
Maria Teresa Landi and colleagues report genomic tumor data for a cohort of patients with lung adenocarcinoma, focusing on implications for tumor initiation and distant metastasis.
Author Summary
Why Was This Study Done?
Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and causes more than half a million deaths worldwide annually.
Genomic studies of LUAD can shed light on tumor initiation and progression and identify potential targets for treatment.
What Did the Researchers Do and Find?
We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), DNA copy number and DNA methylation determination, and transcriptome sequencing in 101 LUAD samples. We replicated major findings using public genomic resources and combined all existing genomic data for an overall analysis of 825 LUAD samples.
We identified two novel driver genes and characterized the driver events and types of mutations that have a stronger role in tumor initiation versus tumor progression.
We found strong associations between DNA methylation and somatic mutation patterns.
The total number of somatic mutations and the fraction of C→T transitions were associated with increased risk of distant metastasis.
What Do These Findings Mean?
We characterized LUAD genomic architecture and linked major genomic features with clinical outcomes.
Tobacco smoking-related mutations appear to have a stronger role in tumor initiation, while mutations associated with endogenous processes are more prominent at a later stage of tumor development and are associated with tumor progression.
Our findings highlight the complexity and heterogeneity of LUAD. In addition to new driver genes, we found some tumors with no exonic mutations in known lung cancer driver genes. This suggests that there are further drivers (genetic or epigenetic) to be identified, and larger numbers of samples need to be studied to fully capture LUAD genomic characteristics.
PMCID: PMC5140047  PMID: 27923066
10.  Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types 
Sampson, Joshua N. | Wheeler, William A. | Yeager, Meredith | Panagiotou, Orestis | Wang, Zhaoming | Berndt, Sonja I. | Lan, Qing | Abnet, Christian C. | Amundadottir, Laufey T. | Figueroa, Jonine D. | Landi, Maria Teresa | Mirabello, Lisa | Savage, Sharon A. | Taylor, Philip R. | Vivo, Immaculata De | McGlynn, Katherine A. | Purdue, Mark P. | Rajaraman, Preetha | Adami, Hans-Olov | Ahlbom, Anders | Albanes, Demetrius | Amary, Maria Fernanda | An, She-Juan | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Angelucci, Emanuele | Ansell, Stephen M. | Arici, Cecilia | Armstrong, Bruce K. | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Becker, Nikolaus | Benavente, Yolanda | Benhamou, Simone | Berg, Christine | Van Den Berg, David | Bernstein, Leslie | Bertrand, Kimberly A. | Birmann, Brenda M. | Black, Amanda | Boeing, Heiner | Boffetta, Paolo | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brinton, Louise | Brooks-Wilson, Angela R. | Bueno-de-Mesquita, H. Bas | Burdett, Laurie | Buring, Julie | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chan, John K. C. | Chang, Ellen T. | Chang, Gee-Chen | Chang, I-Shou | Chang, Jiang | Chang-Claude, Jenny | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chu | Chen, Chung-Hsing | Chen, Constance | Chen, Hongyan | Chen, Kexin | Chen, Kuan-Yu | Chen, Kun-Chieh | Chen, Ying | Chen, Ying-Hsiang | Chen, Yi-Song | Chen, Yuh-Min | Chien, Li-Hsin | Chirlaque, María-Dolores | Choi, Jin Eun | Choi, Yi Young | Chow, Wong-Ho | Chung, Charles C. | Clavel, Jacqueline | Clavel-Chapelon, Françoise | Cocco, Pierluigi | Colt, Joanne S. | Comperat, Eva | Conde, Lucia | Connors, Joseph M. | Conti, David | Cortessis, Victoria K. | Cotterchio, Michelle | Cozen, Wendy | Crouch, Simon | Crous-Bou, Marta | Cussenot, Olivier | Davis, Faith G. | Ding, Ti | Diver, W. Ryan | Dorronsoro, Miren | Dossus, Laure | Duell, Eric J. | Ennas, Maria Grazia | Erickson, Ralph L. | Feychting, Maria | Flanagan, Adrienne M. | Foretova, Lenka | Fraumeni, Joseph F. | Freedman, Neal D. | Beane Freeman, Laura E. | Fuchs, Charles | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | García-Closas, Reina | Gascoyne, Randy D. | Gastier-Foster, Julie | Gaudet, Mia M. | Gaziano, J. Michael | Giffen, Carol | Giles, Graham G. | Giovannucci, Edward | Glimelius, Bengt | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gorlick, Richard | Gross, Myron | Grubb, Robert | Gu, Jian | Guan, Peng | Gunter, Marc | Guo, Huan | Habermann, Thomas M. | Haiman, Christopher A. | Halai, Dina | Hallmans, Goran | Hassan, Manal | Hattinger, Claudia | He, Qincheng | He, Xingzhou | Helzlsouer, Kathy | Henderson, Brian | Henriksson, Roger | Hjalgrim, Henrik | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holford, Theodore R. | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Horn-Ross, Pamela L. | Hosain, G. M. Monawar | Hosgood, H. Dean | Hsiao, Chin-Fu | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Huerta, Jose-Maria | Hung, Jen-Yu | Hutchinson, Amy | Inskip, Peter D. | Jackson, Rebecca D. | Jacobs, Eric J. | Jenab, Mazda | Jeon, Hyo-Sung | Ji, Bu-Tian | Jin, Guangfu | Jin, Li | Johansen, Christoffer | Johnson, Alison | Jung, Yoo Jin | Kaaks, Rudolph | Kamineni, Aruna | Kane, Eleanor | Kang, Chang Hyun | Karagas, Margaret R. | Kelly, Rachel S. | Khaw, Kay-Tee | Kim, Christopher | Kim, Hee Nam | Kim, Jin Hee | Kim, Jun Suk | Kim, Yeul Hong | Kim, Young Tae | Kim, Young-Chul | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert J. | Kogevinas, Manolis | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kricker, Anne | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kweon, Sun-Seog | LaCroix, Andrea | Lawrence, Charles | Lecanda, Fernando | Lee, Victor Ho Fun | Li, Donghui | Li, Haixin | Li, Jihua | Li, Yao-Jen | Li, Yuqing | Liao, Linda M. | Liebow, Mark | Lightfoot, Tracy | Lim, Wei-Yen | Lin, Chien-Chung | Lin, Dongxin | Lindstrom, Sara | Linet, Martha S. | Link, Brian K. | Liu, Chenwei | Liu, Jianjun | Liu, Li | Ljungberg, Börje | Lloreta, Josep | Lollo, Simonetta Di | Lu, Daru | Lund, Eiluv | Malats, Nuria | Mannisto, Satu | Marchand, Loic Le | Marina, Neyssa | Masala, Giovanna | Mastrangelo, Giuseppe | Matsuo, Keitaro | Maynadie, Marc | McKay, James | McKean-Cowdin, Roberta | Melbye, Mads | Melin, Beatrice S. | Michaud, Dominique S. | Mitsudomi, Tetsuya | Monnereau, Alain | Montalvan, Rebecca | Moore, Lee E. | Mortensen, Lotte Maxild | Nieters, Alexandra | North, Kari E. | Novak, Anne J. | Oberg, Ann L. | Offit, Kenneth | Oh, In-Jae | Olson, Sara H. | Palli, Domenico | Pao, William | Park, In Kyu | Park, Jae Yong | Park, Kyong Hwa | Patiño-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Perng, Reury-Perng | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Qian, Biyun | Qiao, You-Lin | Rais, Marco | Riboli, Elio | Riby, Jacques | Risch, Harvey A. | Rizzato, Cosmeri | Rodabough, Rebecca | Roman, Eve | Roupret, Morgan | Ruder, Avima M. | de Sanjose, Silvia | Scelo, Ghislaine | Schned, Alan | Schumacher, Fredrick | Schwartz, Kendra | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Setiawan, Veronica Wendy | Severi, Gianluca | Severson, Richard K. | Shanafelt, Tait D. | Shen, Hongbing | Shen, Wei | Shin, Min-Ho | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesúmaga, Luis | Sihoe, Alan Dart Loon | Skibola, Christine F. | Smith, Alex | Smith, Martyn T. | Southey, Melissa C. | Spinelli, John J. | Staines, Anthony | Stampfer, Meir | Stern, Marianna C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael S. | Su, Jian | Su, Wu-Chou | Sund, Malin | Sung, Jae Sook | Sung, Sook Whan | Tan, Wen | Tang, Wei | Tardón, Adonina | Thomas, David | Thompson, Carrie A. | Tinker, Lesley F. | Tirabosco, Roberto | Tjønneland, Anne | Travis, Ruth C. | Trichopoulos, Dimitrios | Tsai, Fang-Yu | Tsai, Ying-Huang | Tucker, Margaret | Turner, Jenny | Vajdic, Claire M. | Vermeulen, Roel C. H. | Villano, Danylo J. | Vineis, Paolo | Virtamo, Jarmo | Visvanathan, Kala | Wactawski-Wende, Jean | Wang, Chaoyu | Wang, Chih-Liang | Wang, Jiu-Cun | Wang, Junwen | Wei, Fusheng | Weiderpass, Elisabete | Weiner, George J. | Weinstein, Stephanie | Wentzensen, Nicolas | White, Emily | Witzig, Thomas E. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Guoping | Wu, Junjie | Wu, Tangchun | Wu, Wei | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Xu, Ping | Yang, Pan-Chyr | Yang, Tsung-Ying | Ye, Yuanqing | Yin, Zhihua | Yokota, Jun | Yoon, Ho-Il | Yu, Chong-Jen | Yu, Herbert | Yu, Kai | Yuan, Jian-Min | Zelenetz, Andrew | Zeleniuch-Jacquotte, Anne | Zhang, Xu-Chao | Zhang, Yawei | Zhao, Xueying | Zhao, Zhenhong | Zheng, Hong | Zheng, Tongzhang | Zheng, Wei | Zhou, Baosen | Zhu, Meng | Zucca, Mariagrazia | Boca, Simina M. | Cerhan, James R. | Ferri, Giovanni M. | Hartge, Patricia | Hsiung, Chao Agnes | Magnani, Corrado | Miligi, Lucia | Morton, Lindsay M. | Smedby, Karin E. | Teras, Lauren R. | Vijai, Joseph | Wang, Sophia S. | Brennan, Paul | Caporaso, Neil E. | Hunter, David J. | Kraft, Peter | Rothman, Nathaniel | Silverman, Debra T. | Slager, Susan L. | Chanock, Stephen J. | Chatterjee, Nilanjan
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.
Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.
GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
PMCID: PMC4806328  PMID: 26464424
11.  The TERT gene harbors multiple variants associated with pancreatic cancer susceptibility 
Campa, Daniele | Rizzato, Cosmeri | Stolzenberg-Solomon, Rachael | Pacetti, Paola | Vodicka, Pavel | Cleary, Sean P. | Capurso, Gabriele | Bueno-de-Mesquita, H. Bas | Werner, Jens | Gazouli, Maria | Butterbach, Katja | Ivanauskas, Audrius | Giese, Nathalia | Petersen, Gloria M. | Fogar, Paola | Wang, Zhaoming | Bassi, Claudio | Ryska, Miroslav | Theodoropoulos, George E. | Kooperberg, Charles | Li, Donghui | Greenhalf, William | Pasquali, Claudio | Hackert, Thilo | Fuchs, Charles S. | Mohelnikova-Duchonova, Beatrice | Sperti, Cosimo | Funel, Niccola | Dieffenbach, Aida Karina | Wareham, Nicholas J. | Buring, Julie | Holcátová, Ivana | Costello, Eithne | Zambon, Carlo-Federico | Kupcinskas, Juozas | Risch, Harvey A. | Kraft, Peter | Bracci, Paige M. | Pezzilli, Raffaele | Olson, Sara H. | Sesso, Howard D. | Hartge, Patricia | Strobel, Oliver | Małecka-Panas, Ewa | Visvanathan, Kala | Arslan, Alan A. | Pedrazzoli, Sergio | Souček, Pavel | Gioffreda, Domenica | Key, Timothy J. | Talar-Wojnarowska, Renata | Scarpa, Aldo | Mambrini, Andrea | Jacobs, Eric J. | Jamroziak, Krzysztof | Klein, Alison | Tavano, Francesca | Bambi, Franco | Landi, Stefano | Austin, Melissa A. | Vodickova, Ludmila | Brenner, Hermann | Chanock, Stephen J. | Fave, Gianfranco Delle | Piepoli, Ada | Cantore, Maurizio | Zheng, Wei | Wolpin, Brian M. | Amundadottir, Laufey T. | Canzian, Federico
A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT – CLPTM1L gene region on chr5p15.33. Since this region is characterized by low linkage disequilibrium (LD), we sought to identify additional SNPs could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, OR=0.85; 95% CI=0.80–0.90, P=8.3×10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low LD between them (r2=0.07, D´=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (P=3.0×10−5), rs4583925 (P=4.0×10−5) and rs2735948 (P=5.0×10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.
PMCID: PMC4548797  PMID: 25940397
Pancreatic cancer; polymorphisms; telomerase; susceptibility
12.  LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants 
Bioinformatics  2015;31(21):3555-3557.
Summary: Assessing linkage disequilibrium (LD) across ancestral populations is a powerful approach for investigating population-specific genetic structure as well as functionally mapping regions of disease susceptibility. Here, we present LDlink, a web-based collection of bioinformatic modules that query single nucleotide polymorphisms (SNPs) in population groups of interest to generate haplotype tables and interactive plots. Modules are designed with an emphasis on ease of use, query flexibility, and interactive visualization of results. Phase 3 haplotype data from the 1000 Genomes Project are referenced for calculating pairwise metrics of LD, searching for proxies in high LD, and enumerating all observed haplotypes. LDlink is tailored for investigators interested in mapping common and uncommon disease susceptibility loci by focusing on output linking correlated alleles and highlighting putative functional variants.
Availability and implementation: LDlink is a free and publically available web tool which can be accessed at
PMCID: PMC4626747  PMID: 26139635
13.  Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms 
Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P interaction ≤ .001), rs11892031 (UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis.
PMCID: PMC4675099  PMID: 26374428
14.  Mosaic 13q14 deletions in peripheral leukocytes of non-hematologic cancer cases and healthy controls 
Journal of human genetics  2016;61(5):411-418.
Loss of 13q14.3 is a chromosomal event found in approximately 50 percent of B-cell chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) cases. Surveys of somatic alterations in solid tumors have shown sporadic 13q14.3 loss in many different tumor types, but not at high frequency in any specific tumor type. In our recent survey of the single nucleotide polymorphism (SNP) microarray data from 127,000 cancer free or solid tumor cases, we observed mosaic 13q14.3 loss as a common autosomal somatic large structural events (>2 Mb in size) in blood and buccal-derived DNA. Herein, we examined this region more closely investigating structural mosaic events <2 Mb using SNP microarray data in 46,254 non-hematologic cancer cases and 36,229 controls. We detected 60 individuals with 13q14.3 mosaic loss, one mosaic copy neutral uniparental disomy, and 13 individuals with homozygosity. While 13q14.3 loss size was variable, the minimally deleted region (MDR) (chr13:49,590,000-49,983,100; GRCh36) was comparable to what is classically reported in MBL and CLL. Breakpoint analysis of the estimated boundaries reveals enrichment for genes and open chromatin. The frequency of 13q14.3 loss significantly increases with increasing age (P-value=0.028), but was not significantly different between non-hematological cancer cases and controls (0.084% versus 0.058%; P-value=0.19). These findings suggest mosaic 13q14.3 losses accumulate with age. Individuals with detected mosaic 13q14.3 deletions may be early, undetected cases of MBL or CLL, but not necessarily all will develop MBL and CLL.
PMCID: PMC4880507  PMID: 26763882
15.  Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions 
Han, Ying | Hazelett, Dennis J. | Wiklund, Fredrik | Schumacher, Fredrick R. | Stram, Daniel O. | Berndt, Sonja I. | Wang, Zhaoming | Rand, Kristin A. | Hoover, Robert N. | Machiela, Mitchell J. | Yeager, Merideth | Burdette, Laurie | Chung, Charles C. | Hutchinson, Amy | Yu, Kai | Xu, Jianfeng | Travis, Ruth C. | Key, Timothy J. | Siddiq, Afshan | Canzian, Federico | Takahashi, Atsushi | Kubo, Michiaki | Stanford, Janet L. | Kolb, Suzanne | Gapstur, Susan M. | Diver, W. Ryan | Stevens, Victoria L. | Strom, Sara S. | Pettaway, Curtis A. | Al Olama, Ali Amin | Kote-Jarai, Zsofia | Eeles, Rosalind A. | Yeboah, Edward D. | Tettey, Yao | Biritwum, Richard B. | Adjei, Andrew A. | Tay, Evelyn | Truelove, Ann | Niwa, Shelley | Chokkalingam, Anand P. | Isaacs, William B. | Chen, Constance | Lindstrom, Sara | Le Marchand, Loic | Giovannucci, Edward L. | Pomerantz, Mark | Long, Henry | Li, Fugen | Ma, Jing | Stampfer, Meir | John, Esther M. | Ingles, Sue A. | Kittles, Rick A. | Murphy, Adam B. | Blot, William J. | Signorello, Lisa B. | Zheng, Wei | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Nemesure, Barbara | Carpten, John | Leske, M. Cristina | Wu, Suh-Yuh | Hennis, Anselm J. M. | Rybicki, Benjamin A. | Neslund-Dudas, Christine | Hsing, Ann W. | Chu, Lisa | Goodman, Phyllis J. | Klein, Eric A. | Zheng, S. Lilly | Witte, John S. | Casey, Graham | Riboli, Elio | Li, Qiyuan | Freedman, Matthew L. | Hunter, David J. | Gronberg, Henrik | Cook, Michael B. | Nakagawa, Hidewaki | Kraft, Peter | Chanock, Stephen J. | Easton, Douglas F. | Henderson, Brian E. | Coetzee, Gerhard A. | Conti, David V. | Haiman, Christopher A.
Human Molecular Genetics  2015;24(19):5603-5618.
Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10−4–5.6 × 10−3) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10−6) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.
PMCID: PMC4572069  PMID: 26162851
16.  Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses 
PLoS Medicine  2016;13(9):e1002118.
Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers.
Methods and Findings
A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate.
Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.
In a Mendelian randomisation study Pierce and colleagues show a genetic association between adult height and increased risk of colorectal and lung cancer.
Author Summary
Why Was This Study Done?
Several previous observational studies have examined the association between adult height and risk of cancers of the lung, colon/rectum, and prostate; however, it remains unclear whether adult height is indeed related to the risk of these cancers.
What Did the Researchers Do and Find?
We conducted a systematic review and meta-analysis of prospective cohort studies that examined the association between adult height and the risk of colorectal, lung, and prostate cancers.
To overcome inherent limitations of observational study designs, we conducted Mendelian randomization analyses using genetic data generated from a large multi-center consortium study including 47,800 cases and 81,353 controls.
In the meta-analysis of the prospective observational studies, we found a 12% increased risk of colorectal cancer, a 7% increased risk of prostate cancer, and a 6% increased risk of lung cancer for every ten-centimeter increase in height, and this increased risk was corroborated in the Mendelian randomization analyses for colorectal (58%) and lung cancer (10%).
What Do These Findings Mean?
Our study provides strong evidence for an association between adult height and risk of colorectal and lung cancer, and suggests that certain genetic and biological factors that affect height may also affect the risk of these cancers.
However, our meta-analysis was limited to published studies, and the sample size for the Mendelian randomization analysis for colorectal cancer was relatively small, affecting the precision of the risk estimate.
PMCID: PMC5012582  PMID: 27598322
17.  Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite 
Nature genetics  2015;47(9):1073-1078.
Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs1–3. A recent genome-wide association study4 identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls revealed 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1–dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.
PMCID: PMC4591073  PMID: 26214589
EWSR1-FLI1; Ewing sarcoma; germline susceptibility; GGAA microsatellite; EGR2
18.  Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer 
Carcinogenesis  2015;36(9):999-1007.
We identified the minor allele (T) in SNP rs11676348 to have pleiotropic effect on risk of UC and CRC, particularly in tumors with an inflammatory component. Our findings offer the promise of risk stratification of UC patients for developing CRC.
Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E−05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89–0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn’s-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn’s-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.
PMCID: PMC4573660  PMID: 26071399
19.  Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus 
Horne, Hisani N. | Chung, Charles C. | Zhang, Han | Yu, Kai | Prokunina-Olsson, Ludmila | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Muir, Kenneth | Lophatananon, Artitaya | Fasching, Peter A. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marme, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Benitez, Javier | González-Neira, Anna | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Khan, Sofia | Matsuo, Keitaro | Iwata, Hiroji | Dörk, Thilo | Bogdanova, Natalia V. | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Chenevix-Trench, Georgia | Wu, Anna H. | ven den Berg, David | Smeets, Ann | Zhao, Hui | Chang-Claude, Jenny | Rudolph, Anja | Radice, Paolo | Barile, Monica | Couch, Fergus J. | Vachon, Celine | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Marchand, Loic Le | Goldberg, Mark S. | Teo, Soo H. | Taib, Nur A. M. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Shrubsole, Martha | Winqvist, Robert | Jukkola-Vuorinen, Arja | Andrulis, Irene L. | Knight, Julia A. | Devilee, Peter | Seynaeve, Caroline | García-Closas, Montserrat | Czene, Kamila | Darabi, Hatef | Hollestelle, Antoinette | Martens, John W. M. | Li, Jingmei | Lu, Wei | Shu, Xiao-Ou | Cox, Angela | Cross, Simon S. | Blot, William | Cai, Qiuyin | Shah, Mitul | Luccarini, Craig | Baynes, Caroline | Harrington, Patricia | Kang, Daehee | Choi, Ji-Yeob | Hartman, Mikael | Chia, Kee Seng | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Sangrajrang, Suleeporn | Brennan, Paul | Slager, Susan | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hou, Ming-Feng | Swerdlow, Anthony | Orr, Nick | Simard, Jacques | Hall, Per | Pharoah, Paul D. P. | Easton, Douglas F. | Chanock, Stephen J. | Dunning, Alison M. | Figueroa, Jonine D.
PLoS ONE  2016;11(8):e0160316.
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
PMCID: PMC4996485  PMID: 27556229
20.  Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers 
Background: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk.
Methods: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses.
Results: Suggestive pathway-based associations were observed for the overall epigenetic (P-valuePATH = 0.034) and chromatin remodelling (P-valuePATH = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-valueGENE < 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues.
Conclusions: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer.
PMCID: PMC4598798  PMID: 25921222
Epigenetics; chromatin remodelling; DNA methylation; microRNA; oesophageal squamous cell carcinoma; gastric cancer; gastric cardia; gastric non-cardia; SNP; gene-based; pathway-based
21.  Genome-wide association study of colorectal cancer identifies six new susceptibility loci 
Schumacher, Fredrick R. | Schmit, Stephanie L. | Jiao, Shuo | Edlund, Christopher K. | Wang, Hansong | Zhang, Ben | Hsu, Li | Huang, Shu-Chen | Fischer, Christopher P. | Harju, John F. | Idos, Gregory E. | Lejbkowicz, Flavio | Manion, Frank J. | McDonnell, Kevin | McNeil, Caroline E. | Melas, Marilena | Rennert, Hedy S. | Shi, Wei | Thomas, Duncan C. | Van Den Berg, David J. | Hutter, Carolyn M. | Aragaki, Aaron K. | Butterbach, Katja | Caan, Bette J. | Carlson, Christopher S. | Chanock, Stephen J. | Curtis, Keith R. | Fuchs, Charles S. | Gala, Manish | Giovannucci, Edward L. | Gogarten, Stephanie M. | Hayes, Richard B. | Henderson, Brian | Hunter, David J. | Jackson, Rebecca D. | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | LaCroix, Andrea | Laurie, Cathy C. | Laurie, Cecelia A. | Lemire, Mathieu | Levine, David | Ma, Jing | Makar, Karen W. | Qu, Conghui | Taverna, Darin | Ulrich, Cornelia M. | Wu, Kana | Kono, Suminori | West, Dee W. | Berndt, Sonja I. | Bezieau, Stéphane | Brenner, Hermann | Campbell, Peter T. | Chan, Andrew T. | Chang-Claude, Jenny | Coetzee, Gerhard A. | Conti, David V. | Duggan, David | Figueiredo, Jane C. | Fortini, Barbara K. | Gallinger, Steven J. | Gauderman, W. James | Giles, Graham | Green, Roger | Haile, Robert | Harrison, Tabitha A. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Jacobs, Eric | Iwasaki, Motoki | Jee, Sun Ha | Jenkins, Mark | Jia, Wei-Hua | Joshi, Amit | Li, Li | Lindor, Noralene M. | Matsuo, Keitaro | Moreno, Victor | Mukherjee, Bhramar | Newcomb, Polly A. | Potter, John D. | Raskin, Leon | Rennert, Gad | Rosse, Stephanie | Severi, Gianluca | Schoen, Robert E. | Seminara, Daniela | Shu, Xiao-Ou | Slattery, Martha L. | Tsugane, Shoichiro | White, Emily | Xiang, Yong-Bing | Zanke, Brent W. | Zheng, Wei | Le Marchand, Loic | Casey, Graham | Gruber, Stephen B. | Peters, Ulrike
Nature communications  2015;6:7138.
Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
PMCID: PMC4967357  PMID: 26151821
22.  Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data 
Human mutation  2015;36(7):684-688.
We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10−11), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ~3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.
PMCID: PMC4750473  PMID: 25907361
glioma; TP53; rare SNP; TCGA
23.  Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41 
Nature Communications  2016;7:12098.
Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10−7). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.
A common susceptibility haplotype for renal cell carcinoma is located on chromosome 12p12.1. Here, the authors show that the variant rs7132434 alters binding of the AP-1 transcription factor, which increases the expression of BHLHE41 in renal cells.
PMCID: PMC4941055  PMID: 27384883
24.  Germline TP53 Variants and Susceptibility to Osteosarcoma 
The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ2 tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.
PMCID: PMC4651039  PMID: 25896519
25.  Mendelian randomization study of body mass index and colorectal cancer risk 
High body mass index (BMI) is consistently linked to increased risk of colorectal cancer (CRC) for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and CRC.
We used data from 10,226 CRC cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis.
Individuals carrying greater numbers of BMI-increasing alleles had higher CRC risk (per weighted allele OR, 1.31; 95% confidence interval [CI], 1.10–1.57). Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for CRC (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of CRC among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with CRC (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92).
High BMI was associated with increased CRC risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation.
Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of CRC.
PMCID: PMC4490960  PMID: 25976416
Colorectal cancer; Obesity; Epidemiology; Sex; Risk factors

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