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1.  Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study 
PLoS Medicine  2016;13(12):e1002162.
Background
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.
Conclusions
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.
doi:10.1371/journal.pmed.1002162
PMCID: PMC5140047  PMID: 27923066
2.  Lung Cancer Prognosis Before and After Recurrence in a Population-Based Setting 
Background:
Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management.
Methods:
We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non–surgically treated patients.
Results:
Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non–small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients.
Conclusions:
This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events.
doi:10.1093/jnci/djv059
PMCID: PMC4838060  PMID: 25802059
3.  Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue-specific protein interactions 
Human Molecular Genetics  2015;24(25):7406-7420.
Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10−33), epidermal growth factor (P = 1.18 × 10−31) and fibroblast growth factor (P = 2.47 × 10−31) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10−15), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10−9) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10−9). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general.
doi:10.1093/hmg/ddv440
PMCID: PMC4664175  PMID: 26483192
4.  Deciphering associations for lung cancer risk through imputation and analysis of 12 316 cases and 16 831 controls 
European Journal of Human Genetics  2015;23(12):1723-1728.
Recent genome-wide association studies have identified common variants at multiple loci influencing lung cancer risk. To decipher the genetic basis of the association signals at 3q28, 5p15.33, 6p21.33, 9p21 and 12p13.33, we performed a meta-analysis of data from five genome-wide association studies in populations of European ancestry totalling 12 316 lung cancer cases and 16 831 controls using imputation to recover untyped genotypes. For four of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant at these risk loci.
doi:10.1038/ejhg.2015.48
PMCID: PMC4795209  PMID: 25804397
5.  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
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
doi:10.1093/jnci/djv279
PMCID: PMC4806328  PMID: 26464424
6.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
doi:10.1038/ng.3002
PMCID: PMC4074058  PMID: 24880342
8.  The role of haplotype in 15q25.1 locus in lung cancer risk: results of scanning chromosome 15 
Carcinogenesis  2015;36(11):1275-1283.
Summary
The rs588765-rs16969968 haplotype modifies lung cancer risk more than effects from individual variations at rs16969968 or rs588765, and therefore may be a marker of genetic susceptibility to lung cancer even among never-smokers. This knowledge may facilitate our understanding of lung cancer etiology.
The role of haplotypes and the interaction of haplotypes and smoking in lung cancer risk have not been well characterized. We analyzed data from an Italian population-based, case–control study with 1815 lung cancer patients and 1959 healthy controls in discovery, and performed a validation using a case–control study with 2983 lung cancer patients and 3553 healthy controls of European ancestry for replication. Sliding window haplotype analysis within chromosome 15, evaluating 4722250 haplotypes and pair-wise haplotype analysis identified that CHRNA5 rs588765-rs16969968 was the most significant haplotype associated with lung cancer risk (omnibus P = 8.35×10−15 in discovery and 7.26×10−14 in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test P = 0.006 for rs16969968 and 3.83×10−14 for rs588765 in discovery, 0.009 for rs16969968 and 4.62×10−13 for rs588765 in replication, compared with rs588765-rs16969968). Compared with the wild-type homozygous diplotype, CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI 1.46–3.07 in discovery, and OR = 2.01; 95% CI 1.51–2.67 in replication). Even among never-smokers, CA/CA homozygote showed an increased risk of lung cancer with borderline significance in discovery (adjusted OR = 1.75, 95% CI 0.96–3.19) and statistical significance in replication (adjusted OR = 2.10, 95% CI 1.12–3.96), compared with combined genotypes (CG/CG + CG/TG). Accordingly, rs588765-rs16969968 may be a genetic marker to lung cancer risk, even among never-smokers.
doi:10.1093/carcin/bgv118
PMCID: PMC4635666  PMID: 26282330
9.  Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer 
Background:
Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted.
Methods:
We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided.
Results:
We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10–8, and it showed an association with lung cancer (P = 2.01 x 10–6), colorectal cancer (GECCO P = 6.72x10-6; CORECT P = 3.32x10-5), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10-6), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003).
Conclusions:
Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.
doi:10.1093/jnci/djv246
PMCID: PMC4675100  PMID: 26319099
10.  Are Women Who Smoke at Higher Risk for Lung Cancer Than Men Who Smoke? 
American Journal of Epidemiology  2013;177(7):601-612.
Worldwide lung cancer incidence is decreasing or leveling off among men, but rising among women. Sex differences in associations of tobacco carcinogens with lung cancer risk have been hypothesized, but the epidemiologic evidence is conflicting. We tested sex-smoking interaction in association with lung cancer risk within a population-based case-control study, the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study (Lombardy, Italy, 2002–2005). Detailed lifetime smoking histories were collected by personal interview in 2,100 cases with incident lung cancer and 2,120 controls. Odds ratios and 95% confidence intervals for pack-years of cigarette smoking were estimated by logistic regression, adjusted for age, residence area, and time since quitting smoking. To assess sex-smoking interaction, we compared the slopes of odds ratios for logarithm of pack-years in a model for men and women combined. Overall, the slope for pack-years was steeper in men (odds ratio for female-smoking interaction = 0.39, 95% confidence interval: 0.24, 0.62; P < 0.0001); after restriction to ever smokers, the difference in slopes was much smaller (odds ratio for interaction = 0.63, 95% confidence interval: 0.29, 1.37; P = 0.24). Similar results were found by histological type. Results were unchanged when additional confounders were evaluated (e.g., tobacco type, inhalation depth, Fagerström-assessed nicotine dependence). These findings do not support a higher female susceptibility to tobacco-related lung cancer.
doi:10.1093/aje/kws445
PMCID: PMC3657535  PMID: 23425629
case-control studies; lung cancer; sex differences; smoking
11.  Influence of quercetin-rich food intake on microRNA expression in lung cancer tissues 
Background
Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.
Methods
miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR-based analyses, we compared the expression of miRs (n=198) between lung cancer cases consuming high-versus-low quercetin-rich food intake using multivariate ANOVA tests. In family-miR-based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miRs families. We accounted for multiple testing using 10,000 global permutations (significance at p-valueglobal <0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).
Results
Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (p-valueFCS<0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (p-valuesFCS<0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest-and-lowest quercetin-rich food consumers (23 expected by chance; p-valueglobal = 0.047).
Conclusions
We observed differential expression of key biologically functional miRNAs between high-versus-low consumers of quercetin-rich foods in adenocarcinoma cases.
Impact
Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis.
doi:10.1158/1055-9965.EPI-12-0745
PMCID: PMC3538163  PMID: 23035181
12.  A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer 
Scientific Reports  2016;6:34234.
Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10−7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11–1.24; P = 8.31 × 10−9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.
doi:10.1038/srep34234
PMCID: PMC5054367  PMID: 27713484
13.  GSTM1 and GSTT1 copy numbers and mRNA expression in lung cancer 
Molecular carcinogenesis  2012;51(Suppl 1):E142-E150.
Large fractions of the human population do not express GSTM1 and GSTT1 (GSTM1/T1) enzymes because of deletions in these genes. These variations affect xenobiotic metabolism and have been evaluated in relation to lung cancer risk, mostly based on null/present gene models. We measured GSTM1/T1 heterozygous deletions, not tested in genome-wide association studies, in 2120 controls and 2100 cases from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We evaluated their effect on mRNA expression on lung tissue and peripheral blood samples and their association with lung cancer risk overall and by histology types. We tested the null/present, dominant and additive models using logistic regression. Cigarette smoking and gender were studied as possible modifiers. Gene expression from blood and lung tissue cells was strongly down-regulated in subjects carrying GSTM1/T1 deletions by both trend and dominant models (p<0.001). In contrast to the null/present model, analyses distinguishing subjects with 0, 1 or 2 GSTM1/T1 deletions revealed several associations. There was a decreased lung cancer risk in never-smokers (OR=0.44;95%CI=0.23–0.82; p=0.01) and women (OR=0.50;95%CI=0.28–0.90; p=0.02) carrying 1 or 2 GSTM1 deletions. Analogously, male smokers had an increased risk (OR=1.13;95%CI=1.0–1.28; p=0.05) and women a decreased risk (OR=0.78;95%CI=0.63–0.97; p=0.02) for increasing GSTT1 deletions. The corresponding gene-smoking and gene-gender interactions were significant (p<0.05). Our results suggest that decreased activity of GSTM1/T1 enzymes elevates lung cancer risk in male smokers, likely due to impaired carcinogens’ detoxification. A protective effect of the same mutations may be operative in never-smokers and women, possibly because of reduced activity of other genotoxic chemicals.
doi:10.1002/mc.21890
PMCID: PMC3376678  PMID: 22392686
GST; copy numbers; gene expression; lung cancer; smoking and gender differences
14.  A gene expression signature from peripheral whole blood for stage I lung adenocarcinoma 
Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using PWB and paired snap-frozen tumor and non-involved lung tissue samples. Analyses were conducted using unpaired t-tests, linear mixed effects and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (False Discovery Rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus non-involved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer-related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case-control study (n=212) and a tumor-non tumor paired tissue study (n=54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC=0.81, 95% CI=0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future.
doi:10.1158/1940-6207.CAPR-10-0170
PMCID: PMC3188352  PMID: 21742797
microarray gene expression; peripheral blood; lung cancer; stage I
15.  Inherited variation at chromosome 12p13.33 including RAD52 influences squamous cell lung carcinoma risk 
Cancer Discovery  2011;2(2):131-139.
While lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies (GWAS) in Europeans have robustly demonstrated only three polymorphic variations influencing lung cancer risk. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a GWAS of 5,355 European smoking lung cancer cases and 4,344 smoking controls, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 SNPs mapping to 917 genes in the HuGE-defined “inflammation” pathway. We identified a susceptibility locus for squamous cell lung carcinoma (SQ) at 12p13.33 (RAD52, rs6489769), and replicated the association in three independent samples totaling 3,359 SQ cases and 9,100 controls (odds ratio=1.20, Pcombined=2.3×10−8).
Significance
The combination of pathway-based approaches and information on disease specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.
doi:10.1158/2159-8290.CD-11-0246
PMCID: PMC3354721  PMID: 22585858
Lung cancer; histology; squamous cell carcinoma; pathway analysis; RAD52
16.  Genome-wide association study identifies three new melanoma susceptibility loci 
Barrett, Jennifer H | Iles, Mark M | Harland, Mark | Taylor, John C | Aitken, Joanne F | Andresen, Per Arne | Akslen, Lars A | Armstrong, Bruce K | Avril, Marie-Francoise | Azizi, Esther | Bakker, Bert | Bergman, Wilma | Bianchi-Scarrà, Giovanna | Paillerets, Brigitte Bressac-de | Calista, Donato | Cannon-Albright, Lisa A | Corda, Eve | Cust, Anne E | Dębniak, Tadeusz | Duffy, David | Dunning, Alison | Easton, Douglas F | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Giles, Graham G | Hansson, Johan | Hocevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Bart | Jenkins, Mark A | Jönsson, Göran | Kefford, Richard F | Landi, Giorgio | Landi, Maria Teresa | Lang, Julie | Lubiński, Jan | Mackie, Rona | Malvehy, Josep | Martin, Nicholas G | Molven, Anders | Montgomery, Grant W | van Nieuwpoort, Frans A | Novakovic, Srdjan | Olsson, Håkan | Pastorino, Lorenza | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Snowden, Helen | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | Whiteman, David C | Zelenika, Diana | Han, Jiali | Fang, Shenying | Lee, Jeffrey E | Wei, Qingyi | Lathrop, G Mark | Gillanders, Elizabeth M | Brown, Kevin M | Goldstein, Alisa M | Kanetsky, Peter A | Mann, Graham J | MacGregor, Stuart | Elder, David E | Amos, Christopher I | Hayward, Nicholas K | Gruis, Nelleke A | Demenais, Florence | Newton Bishop, Julia A | Bishop, D Timothy
Nature genetics  2011;43(11):1108-1113.
We report a genome-wide association study of melanoma, conducted by GenoMEL, of 2,981 cases, of European ancestry, and 1,982 study-specific controls, plus a further 6,426 French and UK population controls, all genotyped for 317,000 or 610,000 SNPs. The analysis confirmed previously known melanoma susceptibility loci. The 7 novel regions with at least one SNP with p<10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Houston, Texas). Additional replication came from UK and Dutch case-control series. Three of the 7 regions replicated at p<10−3: an ATM missense polymorphism (rs1801516, overall p=3.4×10−9); a polymorphism within MX2 (rs45430, p=2.9×10−9) and a SNP adjacent to CASP8 (rs13016963, p=8.6×10−10). A fourth region near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication. Unlike the previously known regions, the novel loci showed no association with nevus or pigmentation phenotypes in a large UK case-control series.
doi:10.1038/ng.959
PMCID: PMC3251256  PMID: 21983787
17.  Nonsyndromic cleft lip with or without cleft palate and cancer: Evaluation of a possible common genetic background through the analysis of GWAS data 
Genomics Data  2016;10:22-29.
Previous research suggests a genetic overlap between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and cancer. The aim of the present study was to identify common genetic risk loci for NSCL/P and cancer entities that have been reported to co-occur with orofacial clefting. This was achieved through the investigation of large genome-wide association study datasets. Investigations of 12 NSCL/P single nucleotide polymorphisms (SNPs) in 32 cancer datasets, and 204 cancer SNPs in two NSCL/P datasets, were performed. The SNPs rs13041247 (20q12) and rs6457327 (6p21.33) showed suggestive evidence for an association with both NSCL/P and a specific cancer entity. These loci harbor genes of biological relevance to oncogenesis (MAFB and OCT4, respectively). This study is the first to characterize possible pleiotropic risk loci for NSCL/P and cancer in a systematic manner. The data represent a starting point for future research by identifying a genetic link between NSCL/P and cancer.
doi:10.1016/j.gdata.2016.08.017
PMCID: PMC5013250  PMID: 27630819
Cleft lip; Cleft palate; Genome-wide association study; Single nucleotide polymorphism; Cancer
19.  MicroRNA expression differentiates histology and predicts survival of lung cancer 
Purpose
The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histological subtypes and predict survival for non-small cell lung cancer.
Experimental design
We analyzed miR expression in 165 adenocarcinoma (AD) and 125 squamous cell carcinoma (SQ) tissue samples from the Environmental And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t-tests and F-tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards and survival risk prediction models, accounting for demographic and tumor characteristics.
Results
MiR expression profiles strongly differed between AD and SQ (global p<0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were down-regulated in SQ. Major findings were confirmed by QRT-PCR in EAGLE samples and in an independent set of lung cancer cases. In SQ, low expression of miRs down-regulated in the histology comparison was associated with 1.2 to 3.6-fold increased mortality risk. A 5-miR signature significantly predicted survival for SQ.
Conclusions
We identified a miR expression profile that strongly differentiated AD from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches.
doi:10.1158/1078-0432.CCR-09-1736
PMCID: PMC3163170  PMID: 20068076
20.  Alcohol Consumption and Lung Cancer Risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study 
American Journal of Epidemiology  2009;171(1):36-44.
The authors investigated the relation between alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study, a population-based case-control study. Between 2002 and 2005, 2,100 patients with primary lung cancer were recruited from 13 hospitals within the Lombardy region of Italy and were frequency-matched on sex, area of residence, and age to 2,120 randomly selected controls. Alcohol consumption during adulthood was assessed in 1,855 cases and 2,065 controls. Data on lifetime tobacco smoking, diet, education, and anthropometric measures were collected. Adjusted odds ratios and 95% confidence intervals for categories of mean daily ethanol intake were calculated using unconditional logistic regression. Overall, both nondrinkers (odds ratio = 1.42, 95% confidence interval: 1.03, 2.01) and very heavy drinkers (≥60 g/day; odds ratio = 1.44, 95% confidence interval: 1.01, 2.07) were at significantly greater risk than very light drinkers (0.1–4.9 g/day). The alcohol effect was modified by smoking behavior, with no excess risk being observed in never smokers. In summary, heavy alcohol consumption was a risk factor for lung cancer among smokers in this study. Although residual confounding by tobacco smoking cannot be ruled out, this finding may reflect interplay between alcohol and smoking, emphasizing the need for preventive measures.
doi:10.1093/aje/kwp332
PMCID: PMC2800301  PMID: 19933698
alcohol drinking; case-control studies; ethanol; lung neoplasms; risk factors; smoking
21.  Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features 
Genome Biology  2016;17:163.
Background
The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients.
Results
We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors.
Conclusions
Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1021-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1021-1
PMCID: PMC4964003  PMID: 27468850
Air pollution; Tumor stage; 16S rRNA
22.  Family history of cancer and non-malignant lung diseases as risk factors for lung cancer 
Family history (FH) of lung cancer is an established risk factor for lung cancer, but the modifying effect of smoking in relatives has been rarely examined. Also, the role of FH of non-malignant lung diseases on lung cancer risk is not well known. We examined the role of FH of cancer and FH of non-malignant lung diseases in lung cancer risk, overall, and by personal smoking, FH of smoking, and histology in 1,946 cases and 2,116 population-based controls within the Environment And Genetics in Lung cancer Etiology (EAGLE) study. Odds ratios (ORs) and 95% CI from logistic regression were calculated adjusting for age, gender, residence, education, and cigarette smoking. FH of lung cancer in any family member was associated with increased lung cancer risk (OR = 1.57, 95% CI = 1.25–1.98). The odds associated with fathers’, mothers’ and siblings’ history of lung cancer were 1.41, 2.14, and 1.53, respectively. The associations were generally stronger in never smokers, younger subjects, and for the adenocarcinoma and squamous cell carcinoma subtypes. FH of chronic bronchitis and pneumonia were associated with increased (OR =1.49, 95% CI = 1.23–1.80) and decreased (OR = 0.73, 95% CI = 0.61–0.87) lung cancer risk, respectively. FH of lung cancer and FH of non-malignant lung diseases affected lung cancer risk independently, and did not appear to be modified by FH of smoking.
doi:10.1002/ijc.24283
PMCID: PMC2865851  PMID: 19350630
family history; lung cancer; smoking; chronic bronchitis; pneumonia
23.  Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma‐prone families from three continents 
Journal of Medical Genetics  2006;44(2):99-106.
Background
The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.
Methods
These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
Results
Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.
Conclusions
The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
doi:10.1136/jmg.2006.043802
PMCID: PMC2598064  PMID: 16905682
melanoma;  CDKN2A ; multiple primary melanomas; pancreatic cancer
24.  Intakes of red meat, processed meat, and meat-mutagens increase lung cancer risk 
Cancer research  2009;69(3):932-939.
Red and processed meat intake may increase lung cancer risk. However, the epidemiologic evidence is inconsistent and few studies have evaluated the role of meat-mutagens formed during high cooking temperatures. We investigated the association of red meat, processed meat, and meat-mutagen intake with lung cancer risk in Environment And Genetics in Lung cancer Etiology (EAGLE), a population-based case-control study. Primary lung cancer cases (n=2101) were recruited from 13 hospitals within the Lombardy region of Italy examining ~80% of the cases from the area. Non-cancer population controls (n=2120), matched to cases on gender, residence, and age, were randomly selected from the same catchment area. Diet was assessed in 1903 cases and 2073 controls, and used in conjunction with a meat-mutagen database to estimate intake of heterocyclic amines and benzo[a]pyrene. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific tertiles of intake were calculated using unconditional logistic regression. Red and processed meat were positively associated with lung cancer risk (highest-versus-lowest tertile: OR=1.8; 95% CI=1.5–2.2; p-trend<0.001 and OR=1.7; 95% CI=1.4–2.1; p-trend<0.001, respectively); the risks were strongest among never smokers (OR=2.4, 95% CI=1.4–4.0, p-trend=0.001 and OR=2.5, 95% CI=1.5–4.2, p-trend=0.001, respectively). Heterocyclic amines and benzo[a]pyrene were significantly associated with increased risk of lung cancer. When separated by histology, significant positive associations for both meat groups were restricted to adenocarcinoma and squamous cell carcinoma, but not small cell carcinoma of the lung. In summary, red meat, processed meat, and meat-mutagens were independently associated with increased risk of lung cancer.
doi:10.1158/0008-5472.CAN-08-3162
PMCID: PMC2720759  PMID: 19141639
red meat; processed meat; meat-mutagens; cooking methods; lung cancer
25.  Occupational prestige, social mobility and the association with lung cancer in men 
BMC Cancer  2016;16:395.
Background
The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case–control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory.
Methods
We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman’s Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitivity analyses to assess the robustness of our results.
Results
We observed increased lung cancer risk estimates for men with medium (OR = 1.23; 95 % CI 1.13–1.33) and low occupational prestige (OR = 1.44; 95 % CI 1.32–1.57). Although adjustment for smoking and education reduced the associations between occupational prestige and lung cancer, they did not explain the association entirely. Traditional occupational exposures reduced the associations only slightly. We observed small associations with downward prestige trajectories, with ORs of 1.13, 95 % CI 0.88–1.46 for high to low, and 1.24; 95 % CI 1.08–1.41 for medium to low trajectories.
Conclusions
Our results indicate that occupational prestige is independently associated with lung cancer among men.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2432-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2432-9
PMCID: PMC4936282  PMID: 27388894
Life course; Occupational history; Social prestige; Socio-economic status; SYNERGY; Transitions

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