Citations

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.

BACKGROUNDBody weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long‐term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival.METHODSCRC cases diagnosed from 1997 to 2008 were identified through 4 population‐based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow‐up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC‐specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti‐inflammatory drug use, smoking, time between diagnosis and enrollment, and study site.RESULTSAt the 5‐year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median ‐4 kg) weight. Over a median of 5.1 years of subsequent follow‐up (range, 0.3‐9.9 years), 344 participants died (91 of CRC). Long‐term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07‐1.21) and CRC‐specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13‐1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight).CONCLUSIONSWeight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long‐term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701‐4708. © 2017 American Cancer Society.

Abstract The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis. Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with &gt;85% of the bases covered at the target at 50x. So far, targeted sequencing of &gt;1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay. At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC. Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286

BACKGROUNDAlthough previous studies have noted an increased risk of colorectal cancer (CRC) among moderate to heavy alcohol consumers in comparison with nondrinkers, the relation between alcohol consumption and CRC survival remains unclear.METHODSCases of incident invasive CRC diagnosed between 1997 and 2007 were identified via population‐based cancer registries at 4 study sites in the Colon Cancer Family Registry. Study participants completed a risk‐factor questionnaire on prediagnostic behaviors, including wine, beer, and liquor consumption, at the baseline. Prospective follow‐up for survival was conducted for 4966 CRC cases. Cox regression was used to compare nondrinkers with individuals who consumed, on average, 1 or more servings of alcohol per day in the years preceding their CRC diagnosis with respect to overall and disease‐specific survival. Separate analyses by beverage type, stratified by patient and tumor attributes, were also performed. All models were adjusted for the age at diagnosis, sex, study site, year of diagnosis, smoking history, body mass index, and education.RESULTSPrediagnostic beer and liquor consumption was not associated with CRC survival; however, higher levels of wine consumption were modestly associated with a better prognosis overall (CRC‐specific hazard ratio [HR], 0.70, 95% confidence interval [CI], 0.48‐1.03; overall HR, 0.70; 95% CI, 0.53‐0.94). Similar patterns were noted in stratified analyses.CONCLUSIONSThese findings suggest that prediagnostic wine consumption is modestly associated with more favorable survival after CRC. Cancer 2017;123:1035–43. © 2016 American Cancer Society.

Abstract Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P &lt; 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420–4. ©2016 AACR.

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Abstract The completion of The Cancer Genome Atlas (TCGA) project for colorectal cancer (CRC) has enabled a new, focused phase of sequencing tumor samples for which genome-wide genetic, epidemiological, clinical and lifestyle data have been collected. By combining somatic mutational profiles with these aforementioned data, we may identify and report effective prevention and treatment approaches for a broader population of individuals. The advent of targeted deep sequencing approaches using DNA obtained from formalin fixed paraffin embedded tissues has made possible the genetic characterization of the large numbers of patients needed to make such an effort relevant. As a first step, we describe a custom gene panel designed from large-scale studies for targeted deep sequencing, and its application to over 4,200 CR tumors, collected by the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). This study is designed to identify recurrent somatic mutations and copy number alterations (CNAs) for association testing with germline genetic and lifestyle and environmental risk factors for CRC, and thereby identify relevant approaches to impact cancer prevention. The targeted CRC panel includes 205 genes. Genes were primarily selected as significantly mutated genes identified from the Nurses’ Health Study and Health Professional's Follow-up Study (n = 700), and TCGA (n = 525). We also included 15 genes associated with high penetrance germline mutations and augmented the list to include genes in pathways of somatically altered genes, identified by literature review, from public databases and known to be associated with loss of heterozygosity. For these 205 genes, amplification primers were designed to include all coding regions of transcripts that are listed in the UCSC Genome Browser. For regions with CNAs, the TCGA dataset was analyzed to include regions with greater than or equal to 2 copy focal gains or losses that were found in more than 4 or 3 tumors, respectively. Candidate genes in regions with significant CNAs from the TCGA CRC publication (Nature 2012) were also included. For CNAs, 6 to 12 amplicons were designed for each of the 56 selected regions (32 gains and 24 losses). Additional target regions include: 1) 25 microsatellite loci previously used to identify defective DNA mismatch repair and 212 homoploymer repeats. These include microsatellite loci recommended by the NCI Consensus Panel for identifying MSI; 2) amelogenin (for gender); and 3) Fusobacterium to detect a putative CRC-associated pathogen in tumor biopsies. At the AACR annual meeting, we expect to present results for deep sequencing (∼1,000X) of the first 1,000 CR tumors, including any preliminarily identified pathways and subtypes that may provide the basis for association testing with germline genetic and lifestyle and environmental risk factors needed for inferring better approaches to prevention and treatment of CRC. Citation Format: Syed H. Zaidi, Catie Grasso, Jasmine Mu, Eve Shinbrot, Marios Giannakis, Charles Connolly, Ivan Borozan, Hermann Brenner, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Mengmeng Du, Vincent Ferretti, Amy French, Charles Fuchs, Steven Gallinger, Levi Garraway, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen Huyghe, Mathieu Lemire, Elaine Mardis, John McPherson, Polly Newcomb, Lincoln Stein, Wei Sun, Lee Timms, Quang Trinh, David Wheeler, Christina Yung, Niha Zubair, Shuji Ogino, Stephen Thibodeau, Ulrike Peters, Thomas Hudson. Linking the molecular profile of colorectal tumors to germline genetic and environmental risk factors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5221.