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1.  Association of genetic variants in CDK6 and XRCC1 with the risk of dysplastic nevi in melanoma-prone families 
Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each SNP separately, adjusted for age, sex, CMM and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific p-values. Two genes, CDK6 and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent datasets (random effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.
doi:10.1038/jid.2013.316
PMCID: PMC3873368  PMID: 23892592
2.  Constitutive mitochondrial DNA copy number in peripheral blood of melanoma families with and without CDKN2A mutations 
Journal of carcinogenesis & mutagenesis  2014;2014(Suppl 4):006.
Quantitative changes in mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between constitutive mtDNA copy number in blood and the risk of familial cutaneous malignant melanoma (CMM) has not been reported. We measured mtDNA copy number using quantitative PCR in blood-derived DNA from 136 CMM cases and 302 controls in 53 melanoma-prone families (23 segregating CDKN2A germline mutations). MtDNA copy number did not vary by age, sex, pigmentation characteristics, or CMM status. However, germline CDKN2A mutation carriers had significantly higher mean mtDNA copy number compared to non-carriers, particularly among CMM cases (geometric mean mtDNA copy number of 144 and 111 for carrier versus non-carrier, respectively; P= 0.02). When adjusting for age, sex, and familial correlation, having increasing mtDNA copy number was significantly associated with CDKN2A mutation status among CMM cases (OR=1.47, Ptrend=0.024). In particular, individuals with specific CDKN2A mutations with the potential to inactivate or reduce the level of the p16-INK4 reactive oxygen species (ROS) protective function had significantly increased mtDNA copy number levels (P=0.035). Future research in prospective studies is required to validate these findings and to further investigate mtDNA copy number in both blood and melanoma tissues in relation to CMM risk and CDKN2A mutation status.
doi:10.4172/2157-2518.S4-006
PMCID: PMC4326067
Familial melanoma; CDKN2A; mtDNA copy number; peripheral blood
3.  Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression 
E-cadherin is involved in cell-cell adhesion and epithelial-to-mesenchymal transitions (EMT). In cancers, loss or inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to determine if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs) differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on 1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and 6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) was used to follow-up promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more strongly associated with risk of E-cadherin low tumors (OR = 1.30, 95% CI 1.08 – 1.56) than with E-cadherin high tumors (OR = 1.06, 95% CI 0.95 – 1.18; case-only p-heterogeneity (p-het) = 0.05). Findings in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only p-het = 0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors that were ER-positive and of lobular histology. Our results in two independent data sets suggest that rs11249433, which is located between the NOTCH2 and FCGR1B genes within the 1p11.2 locus, is more strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor associations.
doi:10.1007/s10549-013-2771-z
PMCID: PMC4159747  PMID: 24292867
4.  Emerging Concepts in Breast Cancer Risk Prediction 
Developing improved methods for breast cancer risk prediction could facilitate the targeting of interventions to women at highest risk, thereby reducing mortality, while sparing low-risk women the costs and inconvenience of unnecessary testing and procedures. However, currently available risk assessment tools fall short of achieving accurate individual risk prediction, precluding implementation of this approach. Improving these tools will require the identification of new methods of assessing risk and increasing the accuracy of existing risk indicators. We review four emerging topics that may have importance for breast cancer risk assessment: etiological heterogeneity, genetic susceptibility, mammographic breast density and assessment of breast involution.
doi:10.1007/s13669-012-0034-3
PMCID: PMC4262133  PMID: 25506515
Breast Cancer; Risk; Genetics; Mammographic Density; Involution; Etiology; Epidemiology
5.  Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma 
Nature genetics  2014;46(5):482-486.
Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
doi:10.1038/ng.2941
PMCID: PMC4056593  PMID: 24686846
6.  Expression of TGF-β signaling factors in invasive breast cancers: relationships with age at diagnosis and tumor characteristics 
The transforming growth factor beta (TGF-β) pathway can play either a tumor-suppressing or a tumor-promoting role in human breast carcinogenesis. In order to determine whether expression of TGF-β signaling factors varies by age at onset and breast tumor characteristics that have prognostic significance, we undertook a study of 623 women with invasive breast carcinoma enrolled in a population-based case–control study conducted in Poland from 2000 to 2003. TGF-β signaling factors were analyzed by immunohistochemistry in tumor tissue microarrays. We found that most tumors expressed extracellular-TGF-β1 (78%), TGF-β2 (91%), TGF-β3 (93%), TGF-βR2 (72%), and phospho-SMAD2 (61%), whereas intracellular-TGF-β1 was expressed in 32% of tumors. Expression of TGF-β ligands (β1, β2, and β3) was associated with prognostically favorable pathological features including small size, and low grade, and these associations were similar for ER-positive and negative tumors. On the contrary, expression of the receptor TGF-βR2 was primarily associated with small tumor size among ER-negative tumors, while expression of the transcription factor phospho-SMAD2 was associated with positive nodal status among ER-negative tumors. The greater frequency of expression of phospho-SMAD2 in cancers associated with lymph node metastases is consistent with a pro-progression role for TGF-β. In addition, expression of extracellular-TGF-β1 (P = 0.005), TGF-βR2 (P = 8.2E-11), and phospho-SMAD2 (P = 1.3E-8) was strongly associated with earlier age at onset, independent of ER status. Our data provide evidence that TGF-β signaling patterns vary by age and pathologic features of prognostic significance including ER expression. These results warrant analysis in studies of clinical outcomes accounting for age, ER status and treatment.
doi:10.1007/s10549-009-0590-z
PMCID: PMC4159718  PMID: 19937272
Transforming growth factor beta; Breast cancer; Estrogen receptor
7.  Estrogen Receptor and Progesterone Receptor Expression in Normal Terminal Duct Lobular Units Surrounding Invasive Breast Cancer 
Introduction
Molecular and morphological alterations related to carcinogenesis have been found in terminal duct lobular units (TDLUs), the microscopic structures from which most breast cancer precursors and cancers develop, and therefore, analysis of these structures may reveal early changes in breast carcinogenesis and etiologic heterogeneity. Accordingly, we evaluated relationships of breast cancer risk factors and tumor pathology to estrogen receptor (ER) and progesterone receptor (PR) expression in TDLUs surrounding breast cancers.
Methods
We analyzed 270 breast cancer cases included in a population-based breast cancer case-control study conducted in Poland. TDLUs were mapped in relation to breast cancer: within the same block as the tumor (TDLU-T), proximal to tumor (TDLU-PT), or distant from (TDLU-DT). ER/PR was quantitated using image analysis of immunohistochemically stained TDLUs prepared as tissue microarrays.
Results
In surgical specimens containing ER-positive breast cancers, ER and PR levels were significantly higher in breast cancer cells than in normal TDLUs, and higher in TDLU-T than in TDLU-DT or TDLU-PT, which showed similar results. Analyses combining DT-/PT TDLUs within subjects demonstrated that ER levels were significantly lower in premenopausal women vs. postmenopausal women (odds ratio [OR]=0.38, 95% confidence interval [CI]=0.19, 0.76, P=0.0064) and among recent or current menopausal hormone therapy users compared with never users (OR=0.14, 95% CI=0.046–0.43, Ptrend=0.0006). Compared with premenopausal women, TDLUs of postmenopausal women showed lower levels of PR (OR=0.90, 95% CI=0.83–0.97, Ptrend=0.007). ER and PR expression in TDLUs was associated with epidermal growth factor receptor (EGFR) expression in invasive tumors (P=0.019 for ER and P=0.03 for PR), but not with other tumor features.
Conclusions
Our data suggest that TDLUs near breast cancers reflect field effects, whereas those at a distance demonstrate influences of breast cancer risk factors on at-risk breast tissue. Analyses of mapped TDLUs may provide information about the sequence of molecular changes occurring in breast carcinogenesis.
doi:10.1007/s10549-012-2380-2
PMCID: PMC4154606  PMID: 23271326
terminal duct lobular units (TDLUs); estrogen receptor; progesterone receptor; breast cancer; risk factors; tumor characteristics
8.  Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status 
Introduction
Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk.
Methods
We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status.
Results
We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors.
Conclusions
Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors.
doi:10.1186/bcr3689
PMCID: PMC4227137  PMID: 25005139
9.  VTET: a variable threshold exact test for identifying disease-associated copy number variations enriched in short genomic regions 
Copy number variations (CNVs) constitute a major source of genetic variations in human populations and have been reported to be associated with complex diseases. Methods have been developed for detecting CNVs and testing CNV associations in genome-wide association studies (GWAS) based on SNP arrays. Commonly used two-step testing procedures work well only for long CNVs while direct CNV association testing methods work only for recurrent CNVs. Assuming that short CNVs disrupting any part of a given genomic region increase disease risk, we developed a variable threshold exact test (VTET) for testing disease associations of CNVs randomly distributed in the genome using intensity data from SNP arrays. By extensive simulations, we found that VTET outperformed two-step testing procedures based on existing CNV calling algorithms for short CNVs and that the performance of VTET was robust to the length of the genomic region. In addition, VTET had a comparable performance with CNVtools for testing the association of recurrent CNVs. Thus, we expect VTET to be useful for testing disease associations of both recurrent and randomly distributed CNVs using existing GWAS data. We applied VTET to a lung cancer GWAS and identified a genome-wide significant region on chromosome 18q22.3 for lung squamous cell carcinoma.
doi:10.3389/fgene.2014.00053
PMCID: PMC3957064  PMID: 24672538
copy number varination; variable threshold exact test; genome-wide association study; interval-based association test; lung cancer CNV analysis
10.  Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations 
PLoS ONE  2013;8(8):e71121.
Introduction
Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.
Materials and Methods
We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.
Results
We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction.
Discussion
Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.
doi:10.1371/journal.pone.0071121
PMCID: PMC3747185  PMID: 23990928
11.  Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations 
Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors, and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families.
We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (−)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. P-values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p=0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p=0.0006). 28~56% of genotyped SNPs in these genes had single SNP p<0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (−) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.
doi:10.1002/ijc.26231
PMCID: PMC3274649  PMID: 21671477
13.  Duplication of CXC chemokine genes on chromosome 4q13 in a melanoma-prone family 
Pigment cell & melanoma research  2012;25(2):243-247.
Summary
Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggests that the alteration of CXC chemokine genes may confer susceptibility to melanoma.
doi:10.1111/j.1755-148X.2012.00969.x
PMCID: PMC3288577  PMID: 22225770
Familial melanoma; Germline copy number variations; disease susceptibility; CXC chemokines; chromosome 4q13
14.  On the Interplay of Telomeres, Nevi and the Risk of Melanoma 
PLoS ONE  2012;7(12):e52466.
The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
doi:10.1371/journal.pone.0052466
PMCID: PMC3531488  PMID: 23300679
15.  Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium 
Broeks, Annegien | Schmidt, Marjanka K. | Sherman, Mark E. | Couch, Fergus J. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Smith, Letitia D. | Hammet, Fleur | Southey, Melissa C. | Van ’t Veer, Laura J. | de Groot, Renate | Smit, Vincent T.H.B.M. | Fasching, Peter A. | Beckmann, Matthias W. | Jud, Sebastian | Ekici, Arif B. | Hartmann, Arndt | Hein, Alexander | Schulz-Wendtland, Ruediger | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sinn, Hans-Peter | Sohn, Christof | Tchatchou, Sandrine | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Ørsted, David D. | Kaur-Knudsen, Diljit | Milne, Roger L. | Pérez, Jose I. Arias | Zamora, Pilar | Rodríguez, Primitiva Menéndez | Benítez, Javier | Brauch, Hiltrud | Justenhoven, Christina | Ko, Yon-Dschun | Hamann, Ute | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Chang-Claude, Jenny | Wang-Gohrke, Shan | Bremer, Michael | Karstens, Johann H. | Hillemanns, Peter | Dörk, Thilo | Nevanlinna, Heli A. | Heikkinen, Tuomas | Heikkilä, Päivi | Blomqvist, Carl | Aittomäki, Kristiina | Aaltonen, Kirsimari | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana M. | Kataja, Vesa | Auvinen, Päivi | Eskelinen, Matti | Soini, Ylermi | Chenevix-Trench, Georgia | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Holland, Helene | Lambrechts, Diether | Claes, Bart | Vandorpe, Thijs | Neven, Patrick | Wildiers, Hans | Flesch-Janys, Dieter | Hein, Rebecca | Löning, Thomas | Kosel, Matthew | Fredericksen, Zachary S. | Wang, Xianshu | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | McLean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Grenaker Alnæs, Grethe | Kristensen, Vessela | Børresen-Dale, Anne-Lise | Hunter, David J. | Hankinson, Susan E. | Andrulis, Irene L. | Marie Mulligan, Anna | O'Malley, Frances P. | Devilee, Peter | Huijts, Petra E.A. | Tollenaar, Rob A.E.M. | Van Asperen, Christi J. | Seynaeve, Caroline S. | Chanock, Stephen J. | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Figueroa, Jonine | Yang, Xiaohong R. | Hooning, Maartje J. | Hollestelle, Antoinette | Oldenburg, Rogier A. | Jager, Agnes | Kriege, Mieke | Ozturk, Bahar | van Leenders, Geert J.L.H. | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Cox, Angela | Connley, Daniel | Cramp, Helen E. | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W.R. | Dunning, Alison M. | Easton, Douglas F. | Humphreys, Manjeet K. | Caldas, Carlos | Blows, Fiona | Driver, Kristy | Provenzano, Elena | Lubinski, Jan | Jakubowska, Anna | Huzarski, Tomasz | Byrski, Tomasz | Cybulski, Cezary | Gorski, Bohdan | Gronwald, Jacek | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Hou, Ming-Feng | Huang, Chiun-Sheng | Anton-Culver, Hoda | Ziogas, Argyrios | Pharoah, Paul D.P. | Garcia-Closas, Montserrat
Human Molecular Genetics  2011;20(16):3289-3303.
Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER− tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10−18), rs3803662 (16q12) (P = 3.7 × 10−5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10−6 and P = 4.1 × 10−4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.
doi:10.1093/hmg/ddr228
PMCID: PMC3140824  PMID: 21596841
16.  Analysis of terminal duct lobular unit involution in luminal A and basal breast cancers 
Introduction
Involution of terminal duct lobular units (TDLUs), the structures that give rise to most breast cancers, has been associated with reduced breast cancer risk. Data suggest that the etiology and pathogenesis of luminal A and core basal phenotype (CBP) breast cancers differ, but associations with TDLU involution are unknown. Accordingly, we performed a masked microscopic assessment of TDLU involution in benign tissues associated with luminal A and CBP breast cancers diagnosed among women less than age 55 years.
Methods
Cases were participants in a population-based case-control study conducted in Poland. Increased TDLU involution was defined as fewer acini per TDLU or shorter TDLU diameter. Luminal A was defined as estrogen receptor (ER) positive and/or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER2) negative and CBP as negative for ER, PR, and HER2 with expression of basal cytokeratins or epidermal growth factor receptor (EGFR). We performed logistic regression to evaluate associations between TDLU involution and tumor subtypes, adjusted for clinical characteristics and breast cancer risk factors.
Results
Among 232 luminal A and 49 CBP cancers associated with evaluable TDLUs, CBP tumors were associated with significantly greater average number of acini per TDLU (odds ratio (OR) = 3.36, 95% confidence interval (CI) = 1.36 to 8.32, P = 0.009) and larger average TDLU diameter (OR = 2.49, 95% CI = 1.08 to 5.74, P = 0.03; comparing highest to lowest group, adjusted for age and study site).
Conclusions
We suggest that TDLU involution is less marked in benign tissues surrounding CBP as compared to luminal A cancers, which may reflect differences in the etiology and pathogenesis of these tumor subtypes.
doi:10.1186/bcr3170
PMCID: PMC3446399  PMID: 22513288
17.  Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies 
Yang, Xiaohong R. | Chang-Claude, Jenny | Goode, Ellen L. | Couch, Fergus J. | Nevanlinna, Heli | Milne, Roger L. | Gaudet, Mia | Schmidt, Marjanka K. | Broeks, Annegien | Cox, Angela | Fasching, Peter A. | Hein, Rebecca | Spurdle, Amanda B. | Blows, Fiona | Driver, Kristy | Flesch-Janys, Dieter | Heinz, Judith | Sinn, Peter | Vrieling, Alina | Heikkinen, Tuomas | Aittomäki, Kristiina | Heikkilä, Päivi | Blomqvist, Carl | Lissowska, Jolanta | Peplonska, Beata | Chanock, Stephen | Figueroa, Jonine | Brinton, Louise | Hall, Per | Czene, Kamila | Humphreys, Keith | Darabi, Hatef | Liu, Jianjun | Van ‘t Veer, Laura J. | van Leeuwen, Flora E. | Andrulis, Irene L. | Glendon, Gord | Knight, Julia A. | Mulligan, Anna Marie | O’Malley, Frances P. | Weerasooriya, Nayana | John, Esther M. | Beckmann, Matthias W. | Hartmann, Arndt | Weihbrecht, Sebastian B. | Wachter, David L. | Jud, Sebastian M. | Loehberg, Christian R. | Baglietto, Laura | English, Dallas R. | Giles, Graham G. | McLean, Catriona A. | Severi, Gianluca | Lambrechts, Diether | Vandorpe, Thijs | Weltens, Caroline | Paridaens, Robert | Smeets, Ann | Neven, Patrick | Wildiers, Hans | Wang, Xianshu | Olson, Janet E. | Cafourek, Victoria | Fredericksen, Zachary | Kosel, Matthew | Vachon, Celine | Cramp, Helen E. | Connley, Daniel | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W. R. | Dörk, Thilo | Bremer, Michael | Meyer, Andreas | Karstens, Johann H. | Ay, Aysun | Park-Simon, Tjoung-Won | Hillemanns, Peter | Arias Pérez, Jose Ignacio | Rodríguez, Primitiva Menéndez | Zamora, Pilar | Benítez, Javier | Ko, Yon-Dschun | Fischer, Hans-Peter | Hamann, Ute | Pesch, Beate | Brüning, Thomas | Justenhoven, Christina | Brauch, Hiltrud | Eccles, Diana M. | Tapper, William J. | Gerty, Sue M. | Sawyer, Elinor J. | Tomlinson, Ian P. | Jones, Angela | Kerin, Michael | Miller, Nicola | McInerney, Niall | Anton-Culver, Hoda | Ziogas, Argyrios | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Yang, Show-Lin | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Lindblom, Annika | Margolin, Sara | Jakubowska, Anna | Lubiński, Jan | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Gronwald, Jacek | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Jager, Agnes | Kriege, Mieke | Tilanus-Linthorst, Madeleine M. A. | Collée, Margriet | Wang-Gohrke, Shan | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Mononen, Kari | Grip, Mervi | Hirvikoski, Pasi | Winqvist, Robert | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Auvinen, Päivi | Soini, Ylermi | Sironen, Reijo | Bojesen, Stig E. | Dynnes Ørsted, David | Kaur-Knudsen, Diljit | Flyger, Henrik | Nordestgaard, Børge G. | Holland, Helene | Chenevix-Trench, Georgia | Manoukian, Siranoush | Barile, Monica | Radice, Paolo | Hankinson, Susan E. | Hunter, David J. | Tamimi, Rulla | Sangrajrang, Suleeporn | Brennan, Paul | McKay, James | Odefrey, Fabrice | Gaborieau, Valerie | Devilee, Peter | Huijts, P.E.A. | Tollenaar, RAEM. | Seynaeve, C. | Dite, Gillian S. | Apicella, Carmel | Hopper, John L. | Hammet, Fleur | Tsimiklis, Helen | Smith, Letitia D. | Southey, Melissa C. | Humphreys, Manjeet K. | Easton, Douglas | Pharoah, Paul | Sherman, Mark E. | Garcia-Closas, Montserrat
Background
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
Methods
We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
Results
In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
Conclusions
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor–positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
doi:10.1093/jnci/djq526
PMCID: PMC3107570  PMID: 21191117
18.  Lack of germline PALB2 mutations in melanoma-prone families with CDKN2A mutations and pancreatic cancer 
Familial cancer  2011;10(3):545-548.
The presence of pancreatic cancer (PC) in melanoma-prone families has been consistently associated with an increased frequency of CDKN2A mutations, the major high-risk susceptibility gene identified for melanoma. However, the precise relationship between CDKN2A, melanoma and PC remains unknown. We evaluated a recently identified PC susceptibility gene PALB2 using both sequencing and tagging to determine whether PALB2 might explain part of the relationship between CDKN2A, melanoma, and PC. No disease-related mutations were identified from sequencing PALB2 in multiple pancreatic cancer patients or other mutation carrier relatives of PC patients from the eight melanoma-prone families with CDKN2A mutations and PC. In addition, no significant associations were observed between 11 PALB2 tagging SNPs and melanoma risk in 23 melanoma-prone families with CDKN2A mutations or the subset of 11 families with PC or PC-related CDKN2A mutations. The results suggested that PALB2 does not explain the relationship between CDKN2A, melanoma, and pancreatic cancer in these melanoma-prone families.
doi:10.1007/s10689-011-9447-9
PMCID: PMC3244023  PMID: 21614589
CDKN2A; PALB2; familial melanoma; pancreatic cancer; germline mutation
19.  Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations 
Familial cancer  2010;9(4):625-633.
Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A−) for 233 tagging SNPs in 21 genes at 9p21. Single SNP- and gene-based regression analyses were used to assess the risk of CMM, nevi count, skin complexion, and tanning ability associated with these SNPs and genes. We found that SNP rs7023329 in the MTAP gene was associated with number of nevi (Ptrend=0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 (Ptrend=0.002), rs17288067 (Ptrend=0.0009), and rs10813813 (Ptrend=0.005), showed the strongest associations with CMM risk. None of the examined 9p21 SNPs was associated with skin complexion, whereas two SNPs, rs10964862 in IFNW1 (Ptrend=0.003), and rs13290968 in TUSC1 (Ptrend=0.0006), were associated with tanning ability. Gene-based analyses suggested that the ACO1 gene was significantly associated with CMM (P=0.0004); genes IFNW1 (P=0.002) and ACO1 (P=0.0002) were significantly associated with tanning ability. Our findings are consistent with recent proposals that additional 9p21 genes may contribute to CMM susceptibility in CMM-prone families. These genetic variants may, at least partially, exert their effects through nevi and tanning ability.
doi:10.1007/s10689-010-9356-3
PMCID: PMC3233727  PMID: 20574843
melanoma; nevi; chromosome 9p21; SNP; CDKN2A
20.  DNA Hypermethylation of ESR1 and PGR in Breast Cancer: Pathologic and Epidemiologic Associations 
Improved understanding of the etiology of ERα-negative and PR-negative breast cancers may permit improved risk prediction. In vitro studies implicate DNA hypermethylation of the ERα and PR promoters in the pathogenesis of ERα-negative and PR- negative tumors, but results are not definitive. We evaluated 200 invasive breast cancers selected from a population-based case-control study. DNA extracted from fixed tumor tissue cores was tested using MethyLight to assess DNA methylation at 4 CpG islands: ESR1 promoter A and B; PGR promoter A and B; and a CpG shore, ESR1 promoter C. DNA methylation results were compared to levels of ERα, PR, tumor characteristics, and breast cancer risk factors. We observed mild to moderate DNA methylation levels in most tumors for ESR1 promoters A and B and PGR promoter B, and a few tumors showed mild methylation in PGR promoter A. In contrast, ESR1 promoter C showed a wide range of methylation and was weakly correlated with lower expression levels of ERα (β=−0.26; p<0.0001) and PR (β=−0.25; p<0.0001). The percentage of tumors with methylated PGR promoters A and B was significantly higher for tumors with low ERα (A, Fisher’s test p=0.0001; B, p=0.033) and PR levels (A, p=0.0006; B, p=0.001). Our data suggest that the relationships between DNA methylation of ESR1 and PGR promoters and protein expression are weak and unlikely to represent a predominant mechanism of receptor silencing. In contrast to CpG-islands, ESR1 promoter C showed a wider range of methylation levels and inverse associations with ERα and PR expression.
doi:10.1158/1055-9965.EPI-09-0678
PMCID: PMC2783691  PMID: 19861523
21.  Assessment of Automated Image Analysis of Breast Cancer Tissue Microarrays for Epidemiologic Studies 
A major challenge in studies of etiologic heterogeneity in breast cancer has been the limited throughput, accuracy and reproducibility of measuring tissue markers. Computerized image analysis systems may help address these concerns but published reports of their use are limited. We assessed agreement between automated and pathologist scores of a diverse set of immunohistochemical (IHC) assays performed on breast cancer TMAs.
TMAs of 440 breast cancers previously stained for ER-α, PR, HER-2, ER-β and aromatase were independently scored by two pathologists and three automated systems (TMALabII, TMAx, Ariol). Agreement between automated and pathologist scores of negative/positive was measured using the area under the receiver operator characteristics curve (AUC) and weighted kappa statistics (κ) for categorical scores. We also investigated the correlation between IHC scores and mRNA expression levels.
Agreement between pathologist and automated negative/positive and categorical scores was excellent for ER-α and PR (AUC range =0.98-0.99; κ range =0.86-0.91). Lower levels of agreement were seen for ER-β categorical scores (AUC=0.99-1.0; κ=0.80-0.86) and both negative/positive and categorical scores for aromatase (AUC=0.85-0.96; κ=0.41-0.67) and HER2 (AUC=0.94-0.97; κ=0.53-0.72). For ER-α and PR, there was strong correlation between mRNA levels and automated (ρ=0.67-0.74) and pathologist IHC scores (ρ=0.67-0.77). HER2 mRNA levels were more strongly correlated with pathologist (ρ=0.63) than automated IHC scores (ρ=0.41-0.49).
Automated analysis of IHC markers is a promising approach for scoring large numbers of breast cancer tissues in epidemiologic investigations. This would facilitate studies of etiologic heterogeneity which ultimately may allow improved risk prediction and better prevention approaches.
doi:10.1158/1055-9965.EPI-09-1023
PMCID: PMC2852578  PMID: 20332278
Tissue Microarray; Immunohistochemistry; Automated Scoring; Breast Cancer; Reproducibility
22.  Assessment of Automated Image Analysis of Breast Cancer Tissue Microarrays for Epidemiologic Studies 
A major challenge in studies of etiologic heterogeneity in breast cancer has been the limited throughput, accuracy and reproducibility of measuring tissue markers. Computerized image analysis systems may help address these concerns but published reports of their use are limited. We assessed agreement between automated and pathologist scores of a diverse set of immunohistochemical (IHC) assays performed on breast cancer TMAs.
TMAs of 440 breast cancers previously stained for ER-α, PR, HER-2, ER-β and aromatase were independently scored by two pathologists and three automated systems (TMALabII, TMAx, Ariol). Agreement between automated and pathologist scores of negative/positive was measured using the area under the receiver operator characteristics curve (AUC) and weighted kappa statistics (κ) for categorical scores. We also investigated the correlation between IHC scores and mRNA expression levels.
Agreement between pathologist and automated negative/positive and categorical scores was excellent for ER-α and PR (AUC range =0.98-0.99; κ range =0.86-0.91). Lower levels of agreement were seen for ER-β categorical scores (AUC=0.99-1.0; κ=0.80-0.86) and both negative/positive and categorical scores for aromatase (AUC=0.85-0.96; κ=0.41-0.67) and HER2 (AUC=0.94-0.97; κ=0.53-0.72). For ER-α and PR, there was strong correlation between mRNA levels and automated (ρ=0.67-0.74) and pathologist IHC scores (ρ=0.67-0.77). HER2 mRNA levels were more strongly correlated with pathologist (ρ=0.63) than automated IHC scores (ρ=0.41-0.49).
Automated analysis of IHC markers is a promising approach for scoring large numbers of breast cancer tissues in epidemiologic investigations. This would facilitate studies of etiologic heterogeneity which ultimately may allow improved risk prediction and better prevention approaches.
doi:10.1158/1055-9965.EPI-09-1023
PMCID: PMC2852578  PMID: 20332278
Tissue Microarray; Immunohistochemistry; Automated Scoring; Breast Cancer; Reproducibility
23.  T (Brachyury) gene duplication confers major susceptibility to familial chordoma 
Nature genetics  2009;41(11):1176-1178.
Using high-resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families with ≥ 3 cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T gene (Brachyury), which plays an important role in notochord development and is expressed in most sporadic chordomas. Our findings highlight the need to include screening for complex genomic rearrangements in searches for cancer susceptibility genes.
doi:10.1038/ng.454
PMCID: PMC2901855  PMID: 19801981
24.  Identifying rheumatoid arthritis susceptibility genes using high-dimensional methods 
BMC Proceedings  2009;3(Suppl 7):S79.
Although several genes (including a strong effect in the human leukocyte antigen (HLA) region) and some environmental factors have been implicated to cause susceptibility to rheumatoid arthritis (RA), the etiology of the disease is not completely understood. The ability to screen the entire genome for association to complex diseases has great potential for identifying gene effects. However, the efficiency of gene detection in this situation may be improved by methods specifically designed for high-dimensional data. The aim of this study was to compare how three different statistical approaches, multifactor dimensionality reduction (MDR), random forests (RF), and an omnibus approach, worked in identifying gene effects (including gene-gene interaction) associated with RA. We developed a test set of genes based on previous linkage and association findings and tested all three methods. In the presence of the HLA shared-epitope factor, other genes showed weaker effects. All three methods detected SNPs in PTPN22 and TRAF1-C5 as being important. But we did not detect any new genes in this study. We conclude that the three high-dimensional methods are useful as an initial screening for gene associations to identify promising genes for further modeling and additional replication studies.
PMCID: PMC2795981  PMID: 20018074
25.  Lack of inherited mutations of PTPRD in familial melanoma and melanoma-astrocytoma syndrome 
Pigment cell & melanoma research  2009;22(4):489-491.
doi:10.1111/j.1755-148X.2009.00587.x
PMCID: PMC2758084  PMID: 19500277
receptor protein tyrosine phosphatase; p16INK4a; germline mutation; inherited susceptibility; chromosome 9p; familial melanoma

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