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1.  Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study 
Journal of Clinical Oncology  2013;31(33):4252-4259.
Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas.
Patients and Methods
On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined.
Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage.
At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.
PMCID: PMC3821014  PMID: 24127443
2.  Elevated Risk of Prostate Cancer Among Men With Lynch Syndrome 
Journal of Clinical Oncology  2013;31(14):1713-1718.
Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous studies quantifying prostate cancer risk in LS have provided conflicting results.
We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population.
Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03).
The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.
PMCID: PMC3641694  PMID: 23530095
3.  Calculation of Risk of Colorectal and Endometrial Cancer Among Patients with Lynch Syndrome 
Gastroenterology  2009;137(5):1621-1627.
Background & Aims
Lynch Syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias towards overestimated risk.
We studied 147 families with mismatch repair (MMR) gene mutations (55 MLH1, 81 MSH2, and 11 MSH6) identified at 2 U.S. cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared to the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance.
We analyzed 628 cases of CRC, diagnosed at median ages of 42 and 47 years for men and women, respectively. Cumulative risk of CRC was 66.08% (95% confidence interval [CI 59.47%–76.17%) for men and 42.71% (95% CI 36.57%–52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1. There were 155 cases of EC, diagnosed at median age of 47.5 years. Cumulative risk of EC was 39.39% (95% CI 30.78%–46.94%) with overall HR of 39.0% (95% CI 30.4%–50.2%). For women, the cumulative risk of CRC or EC was 73.42% (95% CI 63.76%–80.54%).
Lifetime risks of CRC and EC in MMR gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.
PMCID: PMC2767441  PMID: 19622357
Lynch Syndrome; penetrance; cumulative risk
4.  Adrenocortical Carcinoma Is a Lynch Syndrome–Associated Cancer 
Journal of Clinical Oncology  2013;31(24):3012-3018.
Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC.
Patients and Methods
One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency.
Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene–positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status.
The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.
PMCID: PMC3739861  PMID: 23752102
5.  Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A 
Nature communications  2014;5:4613.
The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P < 5×10−8) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4×10−9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations.
PMCID: PMC4180879  PMID: 25105248
6.  The Risk of Pancreatic Cancer in Families with Lynch Syndrome 
Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer. However, the risk of pancreatic cancer in Lynch Syndrome is uncertain and not quantified.
To estimate pancreatic cancer risk in families with germline mismatch repair gene mutations.
Design, Setting, Patients
Cancer histories of probands and their relatives were evaluated in mismatch repair gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute and University of Michigan Comprehensive Cancer Center. Families enrolled prior to the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared to the general population using modified segregation analysis, with correction for ascertainment.
Main Outcome Measures
Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk
Data on 6,342 individuals from 147 families with mismatch repair gene mutations were analyzed: 21% of families (31/147) reported at least one case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 male, 26 female) with no gender-related difference in age of diagnosis: 51.5 years v. 56.5 years for men and women respectively. The cumulative risk of pancreatic cancer in these families with gene mutations was 1.3% (95% CI: 0.31, 2.32) up to age 50 years and 3.7% (95% CI:1.45, 5.88) up to age 70 years which represents an 8.6-fold increase (95%CI:4.7, 15.7) compared to the general population.
Among 147 families with germline mismatch repair gene mutations, the risk of pancreatic cancer was increased compared to the U.S. population. Individuals with mismatch repair gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of pre-malignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.
PMCID: PMC4091624  PMID: 19861671
7.  Human papillomavirus is not associated with colorectal cancer in a large international study 
Cancer causes & control : CCC  2010;21(5):737-743.
Objective of the study
Recent publications have reported an association between colon cancer and human papillomaviruses (HPV), suggesting that HPV infection of the colonic mucosa may contribute to the development of colorectal cancer.
The GP5+/GP6+ PCR reverse line blot method was used for detection of 37 types of human papilloma-virus (HPV) in DNA from paraffin-embedded or frozen tissues from patients with colorectal cancer (n = 279) and normal adjacent tissue (n = 30) in three different study populations, including samples from the United States (n = 73), Israel (n = 106) and Spain (n = 100). Additionally, SPF10 PCR was run on all samples (n = 279) and the Innogenetics INNO-LiPA assay was performed on a subset of samples (n = 15).
All samples were negative for all types of HPV using both the GP5+/GP6+ PCR reverse line blot method and the SPF10 INNO-LiPA method.
We conclude that HPV types associated with malignant transformation do not meaningfully contribute to adenocarcinoma of the colon.
PMCID: PMC4269349  PMID: 20087645
Human papillomavirus; Colorectal cancer; International study
8.  Transcriptome Profiling Identifies HMGA2 as a Biomarker of Melanoma Progression and Prognosis 
The genetic alterations contributing to melanoma pathogenesis are incompletely defined, and few independent prognostic features have been identified beyond the clinicopathological characteristics of the primary tumor. We used transcriptome profiling of 46 primary melanomas, 12 melanoma metastases, and 16 normal skin (N) samples to find genes associated with melanoma development and progression. Results were confirmed using immunohistochemistry and real-time PCR and replicated in an independent set of 330 melanomas using AQUA analysis of tissue microarray (TMA). Transcriptome profiling revealed that transcription factor HMGA2, previously unrecognized in melanoma pathogenesis, is significantly upregulated in primary melanoma and metastases (P-values=1.2 × 10−7 and 9 × 10−5) compared with N. HMGA2 overexpression is associated with BRAF/NRAS mutations (P=0.0002). Cox proportional hazard regression model and log-rank test showed that HMGA2 is independently associated with disease-free survival (hazard ratio (HR)=6.3, 95% confidence interval (CI)= 1.8–22.3, P=0.004), overall survival (OS) (stratified log-rank P=0.008), and distant metastases–free survival (HR=6.4, 95% CI=1.4–29.7, P=0.018) after adjusting for American Joint Committee on Cancer (AJCC) stage and age at diagnosis. Survival analysis in an independent replication TMA of 330 melanomas confirmed the association of HMGA2 expression with OS (P=0.0211). Our study implicates HMGA2 in melanoma progression and demonstrates that HMGA2 overexpression can serve as an independent predictor of survival in melanoma.
PMCID: PMC4267221  PMID: 23633021
9.  Distinct molecular features of colorectal cancer in Ghana 
Cancer epidemiology  2013;37(5):556-561.
While colorectal cancer (CRC) is common, its incidence significantly varies around the globe. The incidence of CRC in West Africa is relatively low, but it has a distinctive clinical pattern and its molecular characteristics have not been studied. This study is one of the first attempts to analyze molecular, genetic, and pathological characteristics of colorectal cancer in Ghana.
DNA was extracted from microdissected tumor and adjacent normal tissue of 90 paraffin blocks of CRC cases (1997–2007) collected at the University of Ghana. Microsatellite instability (MSI) was determined using fragment analysis of ten microsatellite markers. We analyzed expression of mismatch repair (MMR) proteins by immunohistochemistry and sequenced exons 2 and 3 of KRAS and exon 15 of BRAF.
MSI analysis showed 41% (29/70) MSI-High, 20% (14/70) MSI-Low, and 39% (27/70) microsatellite-stable (MSS) tumors. Sequencing of KRAS exons 2 and 3 identified activating mutations in 32% (24/75) of tumors, and sequencing of BRAF exon 15, the location of the common activating mutation (V600), did not show mutations at codons 599 and 600 in 88 tumors.
Our study found a high frequency of MSI-High colorectal tumors (41%) in Ghana. While the frequency of KRAS mutations is comparable with other populations, absence of BRAF mutations is intriguing and would require further analysis of the molecular epidemiology of CRC in West Africa.
PMCID: PMC4267222  PMID: 23962701
Colorectal cancer; MSI; BRAF; Ghana; Microsatellite instability; West Africa
10.  Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk 
Nature genetics  2014;46(6):533-542.
Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10−8 to 9.22 × 10−21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways.
PMCID: PMC4068797  PMID: 24836286
The annals of applied statistics  2013;7(1):543-569.
The two-phase sampling design is a cost-efficient way of collecting expensive covariate information on a judiciously selected sub-sample. It is natural to apply such a strategy for collecting genetic data in a sub-sample enriched for exposure to environmental factors for gene-environment interaction (G × E) analysis. In this paper, we consider two-phase studies of G × E interaction where phase I data are available on exposure, covariates and disease status. Stratified sampling is done to prioritize individuals for genotyping at phase II conditional on disease and exposure. We consider a Bayesian analysis based on the joint retrospective likelihood of phase I and phase II data. We address several important statistical issues: (i) we consider a model with multiple genes, environmental factors and their pairwise interactions. We employ a Bayesian variable selection algorithm to reduce the dimensionality of this potentially high-dimensional model; (ii) we use the assumption of gene-gene and gene-environment independence to trade-off between bias and efficiency for estimating the interaction parameters through use of hierarchical priors reflecting this assumption; (iii) we posit a flexible model for the joint distribution of the phase I categorical variables using the non-parametric Bayes construction of Dunson and Xing (2009). We carry out a small-scale simulation study to compare the proposed Bayesian method with weighted likelihood and pseudo likelihood methods that are standard choices for analyzing two-phase data. The motivating example originates from an ongoing case-control study of colorectal cancer, where the goal is to explore the interaction between the use of statins (a drug used for lowering lipid levels) and 294 genetic markers in the lipid metabolism/cholesterol synthesis pathway. The sub-sample of cases and controls on which these genetic markers were measured is enriched in terms of statin users. The example and simulation results illustrate that the proposed Bayesian approach has a number of advantages for characterizing joint effects of genotype and exposure over existing alternatives and makes efficient use of all available data in both phases.
PMCID: PMC3935248  PMID: 24587840
Biased sampling; Colorectal cancer; Dirichlet prior; Exposure enriched; sampling; Gene-environment independence; Joint effects; Multivariate categorical distribution; Spike and slab prior
12.  Interaction of Fatty Acid Genotype and Diet on Changes in Colonic Fatty Acids in a Mediterranean Diet Intervention Study 
Cancer prevention research (Philadelphia, Pa.)  2013;6(11):10.1158/1940-6207.CAPR-13-0131.
A Mediterranean diet increases intakes of n-3 and n-9 fatty acids and lowers intake of n-6 fatty acids. This can impact colon cancer risk since n-6 fatty acids are metabolized to pro-inflammatory eicosanoids. The purpose of this study was to evaluate interactions of polymorphisms in the fatty acid desaturase genes, FADS1 and FADS2, and changes in diet on fatty acid concentrations in serum and colon. A total of 108 individuals at increased risk of colon cancer were randomized to either a Mediterranean or a Healthy Eating diet. Fatty acids were measured in both serum and colonic mucosa at baseline and after 6 months. Each individual was genotyped for four single nucleotide polymorphisms in the FADS gene cluster. Linear regression was used to evaluate the effects of diet, genotype and the diet by genotype interaction on fatty acid concentrations in serum and colon. Genetic variation in the FADS genes was strongly associated with baseline serum arachidonic acid (n-6, AA) but serum eicosapentaenoic acid (n-3) and colonic fatty acid concentrations were not significantly associated with genotype. After intervention, there was a significant diet by genotype interaction for AA concentrations in colon. Subjects who had all major alleles for FADS1/2 and were following a Mediterranean diet had 16% lower AA concentrations in the colon after 6 months of intervention than subjects following the Healthy Eating diet. These results indicate that FADS genotype could modify the effects of changes in dietary fat intakes on AA concentrations in the colon.
PMCID: PMC3840911  PMID: 24022589
Fatty acid desaturase; diet-genotype interaction; colon cancer prevention; nutrition
13.  Health Benefits and Cost-Effectiveness of Primary Genetic Screening for Lynch Syndrome in the General Population 
In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice.
PMCID: PMC3793254  PMID: 21088223
14.  Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers 
The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper–Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype.
PMCID: PMC3379723  PMID: 22534780
15.  Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the PI3K-AKT-mTOR pathway 
High-frequency microsatellite instable (MSI-H) tumors account for roughly 15% of colorectal cancers (CRC). Therapeutic decisions for CRC are empirically based and currently do not emphasize molecular subclassification despite of the increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI CRCs using combined gene expression data sets.
Experimental Design
Three expression/query signatures (discovery data set) characterizing MSI-H CRC were matched with information derived from changes induced in cell lines by 164 compounds, using the systems biology tool “Connectivity Map”. A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle and apoptosis effects of validated compounds were evaluated in a panel of cell lines.
Fourteen of the 164 compounds were validated as targeting MSI-H cells lines using the bioinformatics approach; Rapamycin, LY-294002, 17-AAG and Trichostatin-A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by Rapamycin (18.3 vs 4.4 μM, P=0.0824) and LY-294002 (15.02 vs 10.37 μM, P=0.0385) when compared to MSS cells. Preferential activity was also observed in MSH2 and MSH6-mutant cells.
Our study demonstrates that the PI3K-AKT-mTOR pathway is of special relevance in mismatch repair-deficient CRC. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
PMCID: PMC3425357  PMID: 19351759
Microsatellite instability; colorectal cancer; gene expression patterns; rapamycin; mTOR pathway; PI3K inhibitors
16.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
17.  Risk of Colorectal Cancer in Self-Reported Inflammatory Bowel Disease and Modification of Risk by Statin and NSAID Use 
Cancer  2010;117(8):1640-1648.
Background and Aims
Statins and non-steroidal anti-inflammatory drugs (NSAIDs) are associated with reduced risk of CRC in some studies. Our objective was to quantify the relative risk of IBD as risk factor for CRC and to estimate whether this risk may be modified by long term use of NSAIDs or statins.
The Molecular Epidemiology of Colorectal Cancer study is a population based case-control study of incident colorectal cancer in northern Israel and controls matched by age, sex, clinic and ethnicity. Personal histories of IBD and medication use were measured by structured, in-person interview. The relative risk of IBD and effect modification by statins and NSAIDs were quantified by conditional and unconditional logistic regression.
Among 1921 matched pairs of CRC cases and controls, a self-reported history of IBD was associated with a 1.9-fold increased risk of CRC (95% CI, 1.12-3.26). Long-term statin use was associated with a reduced risk of both IBD-associated CRC (OR= 0.07, 95% CI, 0.01-0.78) and non-IBD CRC (OR = 0.49, 95% CI 0.39–0.62). Stratified analysis suggests that statins maybe more protective among those with IBD (ratio of OR = 0.14, 95% CI, 0.01–1.31, p=0.51), although not statistically significant. NSAID use in patients with a history of IBD was suggestive of reduced risk of CRC, but did not reach statistical significance (odds ratio, 0.47, 95% CI, 0.12-1.86).
The risk of CRC is elevated 1.9-fold in patients with IBD. Long term statin use is associated with reduced risk of CRC in patients with IBD.
PMCID: PMC3117060  PMID: 21472711
Inflammatory Bowel Disease (IBD); Colorectal cancer; Statins; Chemoprevention
18.  A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome 
Genetic epidemiology  2010;34(7):756-768.
Anticipation, manifested through decreasing age of onset or increased severity in successive generations, has been noted in several genetic diseases. Statistical methods for genetic anticipation range from a simple use of the paired t-test for age of onset restricted to affected parent-child pairs, to a recently proposed random effects model which includes extended pedigree data and unaffected family members [Larsen et al., 2009]. A naive use of the paired t-test is biased for the simple reason that age of onset has to be less than the age at ascertainment (interview) for both affected parent and child, and this right truncation effect is more pronounced in children than in parents. In this paper, we first review different statistical methods for testing genetic anticipation in affected parent-child pairs that address the issue of bias due to right truncation. Using affected parent-child pair data, we compare the paired t-test with the parametric conditional maximum likelihood approach of Huang and Vieland [1997] and the nonparametric approach of Rabinowitz and Yang [1999] in terms of Type I error and power under various simulation settings and departures from the modeling assumptions. We especially investigate the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation in one of the three main mismatch repair (MMR) genes. In contrast to the clinic-based population, we re-analyze data on a population-based Lynch syndrome cohort, derived from the Danish HNPCC-register. Both datasets indicate evidence of genetic anticipation in Lynch syndrome. We then expand our review to incorporate recently proposed statistical methods that consider family instead of affected pairs as the sampling unit. These prospective censored regression models offer additional flexibility to incorporate unaffected family members, familial correlation and other covariates into the analysis. An expanded dataset from the Danish HNPCC-register is analyzed by these alternative set of methods.
PMCID: PMC3894615  PMID: 20878717
Cox proportional hazards model; Hereditary nonpolyposis colorectal cancer; Mismatch repair genes; Multiplex ascertainment; Random effects; Sandwich estimator
Gastroenterology  2010;139(2):439-447.e1.
Backgound & Aims
Germline mutations of the APC gene are the pathogenic cause of most cases of familial adenomatous polyposis (FAP) and a lesser proportion of attenuated FAP (AFAP). Systematic analysis of APC at the RNA level may provide insight into the pathogenicity of identified mutations and uncover the molecular basis of FAP/AFAP in families without identifiable mutations. Here, we analyzed the prevalence of imbalances in the allelic expression of APC in polyposis families with germline mutations in the gene and without detectable mutations in APC or and MUTYH.
Allele-specific expression (ASE) was determined by single nucleotide primer extension using an exon 11 polymorphism as an allele-specific marker. In total, 52 APC-mutation-positive (36 families) and 24 APC/MUTYH-mutation-negative (23 families) informative patients were analyzed. Seventy-six controls were also included.
Of the APC-mutation-positive families, most of those in which the mutation was located before the last exon of the gene (12 of 14) showed ASE imbalance, which is consistent with a mechanism of nonsense-mediated decay (NMD). Of the APC/MUTYH mutation-negative families, two (9%) showed ASE imbalance as a hallmark of the putative pathogenic cause of the disease. Normal allele expression was restored after treatment of short-term cultured lymphocytes with puromycin, supporting the NMD hypothesis.
ASE analysis may be an indicator of pathogenicity for some cases of FAP and AFAP in which APC mutations are not found. ASE might also be useful for prioritizing the order in which different areas of APC should be tested. Our results underline the importance of RNA-level studies in molecular diagnosis of FAP.
PMCID: PMC2910837  PMID: 20434453
Familial adenomatous polyposis; Allele-specific expression; APC; Nonsense-mediated decay
20.  Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome 
Gynecologic oncology  2012;127(3):544-551.
Due to the increased lifetime risk of endometrial cancer (EC), guidelines recommend that women with Lynch syndrome (LS) age ≥35 undergo annual EC surveillance or prophylactic hysterectomy (PH). The aim of this study was to examine the uptake of these risk-reducing strategies.
The study population included women meeting clinical criteria for genetic evaluation for LS. Data on cancer risk-reducing behaviors were collected from subjects enrolled in two distinct studies: (1) a multicenter cross-sectional study involving completion of a one-time questionnaire, or (2) a single-center longitudinal study in which subjects completed questionnaires before and after undergoing genetic testing. The main outcome was uptake of EC risk-reducing practices.
In the cross-sectional cohort, 58/77 (75%) women at risk for LS-associated EC reported engaging in EC risk-reduction. Personal history of genetic testing was associated with uptake of EC surveillance or PH (OR 17.1; 95% CI 4.1–70.9). Prior to genetic testing for LS, 26/40 (65%) women in the longitudinal cohort reported engaging in EC risk-reduction. At one-year follow-up, 16/16 (100%) mismatch repair (MMR) gene mutation carriers were adherent to guidelines for EC risk-reduction, 9 (56%) of whom had undergone PH. By three-year follow-up, 11/16 (69%) MMR mutation carriers had undergone PH. Among women with negative or uninformative genetic test results, none underwent PH after testing.
Genetic testing for LS is strongly associated with uptake of EC risk-reducing practices. Women found to have LS in this study underwent prophylactic gynecologic surgery at rates comparable to those published for BRCA1/2 mutation carriers.
PMCID: PMC3496001  PMID: 22940489
21.  MLH1 methylation screening is effective in identifying epimutation carriers 
European Journal of Human Genetics  2012;20(12):1256-1264.
Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.
PMCID: PMC3499751  PMID: 22763379
Lynch syndrome; constitutional epimutation; MLH1; methylation; MS-MLPA; pyrosequencing
22.  Disclosing Individual CDKN2A Research Results to Melanoma Survivors: Interest, Impact, and Demands on Researchers 
Whether to return individual research results from cancer genetics studies is widely debated, but little is known about how participants respond to results disclosure or about its time and cost burdens on investigators.
We recontacted participants at one site of a multicenter genetic epidemiologic study regarding their CDKN2A gene test results and implications for melanoma risk. Interested participants were disclosed their results by telephone and followed for 3 months.
Among 39 patients approached, 27 were successfully contacted, and 19 (70% uptake) sought results, including three with mutations. Prior to disclosure, participants endorsed numerous benefits of receiving results (mean = 7.7 of 9 posed), including gaining information relevant to their children’s disease risk. Mean psychological well-being scores did not change from baseline, and no decreases to melanoma prevention behaviors were noted. Fifty-nine percent of participants reported that disclosure made participation in future research more likely. Preparation for disclosure required 40 minutes and $611 per recontact attempt. An additional 78 minutes and $68 was needed to disclose results.
Cancer epidemiology research participants who received their individual genetic research results showed no evidence of psychological harm or false reassurance from disclosure and expressed strong trust in the accuracy of results. Burdens to our investigators were high, but protocols may differ in their demands and disclosure may increase participants’ willingness to enroll in future studies.
Providing individual study results to cancer genetics research participants poses potential challenges for investigators, but many participants desire and respond positively to this information.
PMCID: PMC3833711  PMID: 21307304
23.  Smoking, gender, and ethnicity predict somatic BRAF mutations in colorectal cancer 
Approximately 5 – 15% of all CRCs have an activating BRAF somatic mutation, which may be associated with a distinct risk profile compared to tumors without BRAF mutations. Here, we measured the prevalence and epidemiologic correlates of the BRAF V600E somatic mutation in cases collected as a part of a population-based case-control study of colorectal cancer in northern Israel. The prevalence of BRAF V600E was 5.0% in this population, and the mutation was more likely to be found in tumors from cases who were of Ashkenazi Jewish descent (OR = 1.87, 95% C.I., 1.01 – 3.47), female (OR = 1.97, p = 1.17 – 3.31) and older (73.8 years vs. 70.3 years, p < 0.001). These results were similar when restricting to only tumors with microsatellite instability. Whether or not smoking was associated with a BRAF somatic mutation depended on gender. While men were less likely to have a tumor with a BRAF somatic mutation, men who smoked were much more likely to have a tumor with a somatic BRAF mutation (ORinteraction = 4.95, 95% C.I., 1.18 – 20.83) than women who never smoked. We note the strong heterogeneity in the reported prevalence of the BRAF V600E mutation in studies of different ethnicities, with a lower prevalence in Israel than other Western populations, but a higher prevalence among Jewish than non-Jewish Israeli cases. Epidemiologic studies of colorectal cancer should incorporate somatic characteristics to fully appreciate risk factors for this disease.
PMCID: PMC2872124  PMID: 20200438
Colorectal cancer; somatic mutations; BRAF; epidemiology
24.  Survival for patients with single and multiple primary melanomas in the GEM study 
JAMA dermatology (Chicago, Ill.)  2013;149(8):10.1001/jamadermatol.2013.4581.
Little is known about survival after a diagnosis of a second or higher order (multiple) primary melanoma. We aimed to determine whether survival after diagnosis was better in patients with multiple primary melanomas (MPM) than with single primary melanomas (SPM), as suggested in a recent study.
Survival analysis with median follow-up of 7.6 years (range 0.4-10.6).
The Genes, Environment and Melanoma (GEM) study enrolled incident cases of melanoma notified to population-based cancer registries in Australia, Canada, Italy and the USA. MPM were ascertained over a longer period than SPM.
2372 patients with SPM and 1206 with MPM.
Main outcome measures
Melanoma-specific fatality hazard ratios (HR) and confidence intervals (CI) associated with clinical and pathologic characteristics of SPM, MPM and both together in Cox regression models.
Thickness was the main determinant of fatality (HR for >4mm=7.68, 95% CI 4.46 to 13.23); other independent predictors were ulceration, mitoses and scalp location. After adjustment for these other predictors, there was little difference in fatality between MPM and SPM (HR for MPM relative to SPM=1.24, 95% CI 0.91 to 1.69; P = .18). Thicker SPM, however, had higher fatality (HR for >4mm=13.56, 95% CI 6.47-28.40) than thicker MPM (HR for >4mm=2.93, 95% CI 1.17-7.30).
While overall fatalities from SPM and MPM were similar, relative fatality for thick SPM was greater than for thick MPM. This finding may offer support for a difference in outcome between patients with SPM and MPM that is worth further exploration.
PMCID: PMC3815536  PMID: 23784017
GEM; MPM; SPM; pathology characteristics; fatality; survival
25.  Breast Cancer Phenotype in Women with TP53 Germline Mutations: a Li Fraumeni Syndrome Consortium Effort 
Breast cancer research and treatment  2012;133(3):1125-1130.
Breast cancer is the most common tumor in women with Li Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 carriers have recently been reported to more often be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to expand this small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS.
Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutations carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade and hormone receptor status was assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH.
The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22–46). Of the invasive cancers, 84% were positive for ER and/or PR; 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER, and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases.
This report of the phenotype of breast cancers from women with Li Fraumeni syndrome nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in Li Fraumeni syndrome are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may improve outcomes for women with LFS-associated breast cancer.
PMCID: PMC3709568  PMID: 22392042
Breast Cancer; Li Fraumeni Syndrome; TP53 mutations; HER2; hormone receptors

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