Hopper, John L.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Background: Smoking has been associated with colorectal cancer (CRC) risk; but limited evidence has shown the association between smoking and molecular subtypes of CRC. Methods: We analyzed 9,422 CRC cases and 9,950 controls from 10 observational studies. Multinomial logistic regression analysis was performed to assess the association between sex-study-specific quartiles of pack years of smoking and risk of CRC molecular subtypes, using non-smokers as reference group, adjusting for age, sex, and study. Known oncogenic mutations in four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutations, KRAS mutations, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. Case-only analysis was also performed to estimate heterogeneity in risk of molecular subtypes of CRC. Results: Compared with controls, higher pack years of smoking were statistically significantly associated with increased CRC risk when stratified, individually, by all four markers, and the associations got stronger with higher quartiles pack years (p-trend<0.001). Associations between smoking and CRC risk also differed significantly among molecular subtypes. Compared to nonsmokers, the risk of BRAFmut CRC was 83% higher for smokers within the highest quartile of pack-years (OR=1.83; 95% CI: 1.50, 2.25), and 29% higher for BRAFwt CRC (OR=1.29; 95% CI: 1.17, 1.43; Ratio of ORs (ROR)=1.45; 95% CI: 1.18, 1.17; p=3.45x10-4). Similarly, heavy pack-years of smoking was associated with almost two times higher risk of CIMP-high CRC (OR=1.93; 95% CI: 1.60, 2.31), but only 33% higher risk of CIMP-low/negative CRC (OR=1.33; 95% CI: 1.19, 1.48; ROR=1.49; 95% CI: 1.24, 1.79; p=1.72x10-5). The association between smoking and CRC was also stronger in MSI-high tumors (ORMSI-H=1.65; 95% CI: 1.36, 2.00; ORMSI-L/MSS=1.37; 95% CI: 1.23, 1.52; ROR=1.22; 95% CI: 1.00, 1.48; p=0.046). In contrast, the association between smoking and CRC risk was stronger for KRASwt (OR=1.43; 95% CI: 1.27, 1.60), than KRASmut tumors (OR=1.18; 95% CI: 1.02, 1.37; ROR=0.83; 95% CI: 0.71, 0.97; p =0.016). When combining tumor markers, smoking was found to be significantly associated with higher risk of colorectal tumors from the serrated pathway. Conclusion: In this largest study with a total of 19,372 subjects, we found that heavier pack years of smoking was associated with increased risk of all CRC molecular subtypes. Smokers with heavier pack-years of smoking had particularly higher risk of CRC subtypes with BRAF mutation and CIMP-high, suggesting smoking may be particularly involved in the development of these subtypes of colorectal tumor. Citation Format: Xiaoliang Wang, Efrat Amitay, Barbara L. Banbury, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Jenny Chang-Claude, Steven J. Gallinger, Graham G. Giles, Tabitha A. Harrison, John L. Hopper, Mark A. Jenkins, Yi Lin, Reiko Nishihara, Polly A. Newcomb, Shuji Ogino, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Steven N. Thibodeau, Bethany Van Guelpen, Michael O. Woods, Li Hsu, Michael Hoffmeister, Ulrike Peters. Smoking is associated with risks of molecular subtypes of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 630.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p‐value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p‐value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p‐value of 5.8 × 10−6. Ninety‐four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis‐eQTL suggesting possible mechanisms of carcinogenesis.

Abstract Aim: We aimed to develop a comprehensive Colorectal cancer Risk Prediction Tool (CRiPT). To achieve this, it is necessary to incorporate germline mutations in the DNA mismatch repair genes and MUTYH to account for a proportion of the familial aggregation of colorectal cancer. Population prevalence of these mutations and the genetic and environmental causes of the remaining familial aggregation, however, are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the USA, Canada and Australia, and screened probands for mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, and MUTYH. We fitted modified segregation analysis models to the cancer history of first-degree relatives, conditional on the age at diagnosis of the proband, using the software MENDEL. We determined the genetic model that best explained the familial aggregation of colorectal cancer by estimating the prevalence of mutations in the known susceptibility genes, the prevalence of and hazard ratio for unmeasured high-risk gene mutations, and the variance of the unmeasured polygenic component, using a χ2 goodness-of-fit test. Results: The best fitting model was a mixed dominant model with the polygenic standard deviation varying by age. Under that model, we estimated 1 in 279 of the population carry mutations in the mismatch repair genes (MLH = 1 in 1946, MSH2 = 1 in 2841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations in unknown major gene(s) which are associated with on average a 31-fold increased risk of colorectal cancer. The estimated variance of the polygenic component decreased from 1.8 for age <40 years to 0.7 for age ≥70 years (equivalent to a sibling relative risk of 5.1 and 1.3, respectively). There was good internal consistency in the best fitting model; i.e., predicted and observed numbers were close. Conclusion: CRiPT is a comprehensive prediction model that incorporates both known and unknown major genes and polygenes. CRiPT can provide the probabilities of having a mutation in a DNA mismatch repair gene or MUTYH as well as estimate future risk (e.g., 5-year risk) of developing colorectal cancer. This model is similar to the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) that calculates for women the probabilities of carrying a BRCA1 or BRCA2 mutation and their future risk of developing breast and ovarian cancer based on their family history. Further work will include measured environmental factors and genetic variants to CRiPT, and it will be useful for genetic counselling and targeted colorectal cancer screening in clinical practices. This abstract is also being presented as Poster B04. Citation Format: Aung Ko Win, Mark A. Jenkins, James G. Dowty, Antonis C. Antoniou, Andrew Lee, Yingye Zheng, Noralane M. Lindor, Polly A. Newcomb, John L. Hopper, Robert J. MacInnis. Development of a comprehensive colorectal cancer risk prediction tool (CRiPT) incorporating known and unknown major genes and polygenes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR10.

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR10) of the Conference Proceedings. Citation Format: Aung Ko Win, Mark A. Jenkins, James G. Dowty, Antonis C. Antoniou, Andrew Lee, Yingye Zheng, Noralane M. Lindor, Polly A. Newcomb, John L. Hopper, Robert J. MacInnis. Development of a comprehensive colorectal cancer risk prediction tool (CRiPT) incorporating known and unknown major genes and polygenes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B04.

Abstract Background: Radiologically dense area (DA) on a mammogram represents the stromal and epithelial tissue in the breast, while non-dense area (NDA) represents adipose tissue. Quantitative measurements of DA, NDA as well as the proportion of dense area in the breast (percent density, PD) adjusted for age and body mass index (BMI) have all been associated with breast cancer (BC) risk. Previous genome-wide association studies (GWAS) have identified genetic loci that show association with both mammographic density (MD) phenotypes and BC, but little is known about the genome-wide and local genetic correlation between MD phenotypes and BC. Methods: We estimated the genome-wide and local genetic correlation between MD phenotypes adjusted for age and BMI and BC, leveraging GWAS summary statistics for MD phenotypes based on 12,866 women (MODE consortium) and for BC based on 122,977 cases and 105,974 controls (BCAC consortium). We also conducted partitioned heritability analysis to identify specific functional annotations that contribute to MD heritability. Results: We observed a negative genetic correlation between DA and NDA (-0.62, p=0.002). Both DA and PD showed positive genetic correlations with overall BC (DA: rg=0.24, p=0.004; PD: rg=0.27, p=0.0001), estrogen receptor-positive (ER+) BC (DA: rg=0.23, p=0.005; PD: rg=0.23, p=0.001), and ER- BC (DA: rg=0.26, p=0.01; PD: rg=0.32, p=0.0006). In contrast, NDA showed a nonsignificant negative genetic correlation with BC (rg=-0.11, p=0.21). Local genetic correlation analyses between MD phenotypes and BC reflected known findings including positive correlation at 10q21 region between both PD and DA and BC (both p<5x10-7), negative correlation at 22q13.1 between DA and BC (p=4.6x10-6), and positive correlation at 8p11.23 between NDA and BC (p=2.8x10-6). Two known BC regions that have not previously been associated with MD showed suggestive genetic correlations between BC and DA: 1q21.2 (negative genetic correlation, p=1.3x10-4) and 12q21.31 (positive genetic correlation, p=6.7x10-4). In exploratory analyses estimating the genome-wide genetic correlation between MD and hormone-related phenotypes in UK Biobank (n=337,199), we observed nominally significant positive genetic correlations between PD and benign mammary dysplasia (rg=0.45, p=0.01), NDA and endometriosis (rg=0.45, p=0.02), and negative genetic correlation between NDA and menstrual cycle length (rg=-0.30, p=0.05). We identified multiple functional annotations that contribute to MD heritability including histone mark H3K27ac that marks active enhancers (~2,5-fold enrichment in heritability for both DA and NDA) and DNAsel Hypersensitive Sites (DHS, 9.1-fold enrichment in heritability for DA). Conclusion: Our results provide evidence of shared genetic basis between mammographic density and breast cancer. Citation Format: Hongjie Chen, Julie Douglas, William Gordon, Deborah Thompson, Fergus Couch, Peter Fasching, Per Hall, John Hopper, Gertraud Maskarenic, Marina Pollan, Jennifer Stone, Rulla Tamimi, Sara Lindstroem. Evidence for a shared genetic basis between breast cancer and mammographic density phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 224.

Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk in people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n = 807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self‐reported physical activity in three age‐periods (20–29, 30–49 and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET‐hr/week) during the age‐period of cancer diagnosis or censoring (near‐term exposure) and across all age‐periods preceding cancer diagnosis or censoring (long‐term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near‐term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs. <3.5 MET‐hr/week, 0.71; 95% CI, 0.53–0.96). The strength and direction of associations were similar for long‐term physical activity, although the associations were not nominally significant. Our results suggest that physical activity is inversely associated with the risk of colorectal cancer for people with Lynch syndrome; however, further confirmation is warranted. The potential modifying effect of physical activity on colorectal cancer risk in people with Lynch syndrome could be useful for risk prediction and support counseling advice for lifestyle modification to reduce cancer risk.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.