Newcomb, Polly A.

AbstractBackground: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes.Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS).Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03).Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes.Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.

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.

AbstractBackgroundThe extent to which participants act to clinically verify research results is largely unknown. This study examined whether participants who received Lynch syndrome (LS)‐related findings pursued researchers’ recommendation to clinically verify results with testing performed by a CLIA‐certified laboratory.MethodsThe Fred Hutchinson Cancer Research Center site of the multinational Colon Cancer Family Registry offered non‐CLIA individual genetic research results to select registry participants (cases and their enrolled relatives) from 2011 to 2013. Participants who elected to receive results were counseled on the importance of verifying results at a CLIA‐certified laboratory. Twenty‐six (76.5%) of the 34 participants who received genetic results completed 2‐ and 12‐month postdisclosure surveys; 42.3% of these (11/26) participated in a semistructured follow‐up interview.ResultsWithin 12 months of result disclosure, only 4 (15.4%) of 26 participants reported having verified their results in a CLIA‐certified laboratory; of these four cases, all research and clinical results were concordant. Reasons for pursuing clinical verification included acting on the recommendation of the research team and informing future clinical care. Those who did not verify results cited lack of insurance coverage and limited perceived personal benefit of clinical verification as reasons for inaction.ConclusionThese findings suggest researchers will need to address barriers to seeking clinical verification in order to ensure that the intended benefits of returning genetic research results are realized.

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 >85% of the bases covered at the target at 50x. So far, targeted sequencing of >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

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

451 Background: Classifications for molecular subtypes of colorectal cancer based on microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and somatic mutations in BRAFV600E and KRAS have been proposed to reflect distinct pathways of colorectal tumorigenesis. We assessed the relationship between these subtype classifications and colorectal cancer survival in a population-based study. Methods: Tumor-markers were evaluated in incident colorectal cancer cases diagnosed between 1997-2007 in western Washington State. Cases were classified into pathway-based subtypes according to the following tumor-marker combinations: (1) traditional pathway [microsatellite stable / low MSI (MSS/MSI-L), non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 631]; (2) MSI-high serrated (MSI-high, CIMP-positive, BRAF-mutated, KRAS-wildtype, N=100); (3) MSS/MSI-L serrated (MSS/MSI-L, CIMP-positive, BRAF-mutated, KRAS-wildtype, n = 55); (4) alternate pathway (MSS/MSI-L, non-CIMP, BRAF-wildtype, KRAS-mutated, n = 353); and (5) MSI-high familial (MSI-high, non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 50). Multiple-imputation was used to classify tumor-marker status for cases with missing data on one to three markers. Differences in survival across subtypes were assessed through multivariable-adjusted Cox regression. Results: Relative to cases of the predominant traditional pathway subtype, cases with MSS/MSI-L serrated and alternate pathway tumor subtypes experienced statistically significantly worse disease-specific survival [hazard ratio (HR) = 2.25, 95% confidence interval (CI): 1.50-3.36 and HR = 1.39, 95% CI: 1.12-1.71, respectively]; cases with MSI-high familial tumors had the most favorable disease-specific prognosis (HR = 0.28, 95% CI: 0.12-0.64). With respect to overall survival, associations were similar but slightly attenuated. Conclusions: In this large, population-based study, colorectal cancer subtype classifications based on integrated pathways were associated with marked differences in survival, highlighting the significance of molecular heterogeneity in colorectal cancer.

600 Background: Experimental and clinical evidence suggests that constitutively decreased Transforming Growth Factor Beta type I receptor (TGFBR1) signaling predisposes to colorectal cancer (CRC) development. However, associations between TGFBR1 variants and CRC risk in case-control studies have been inconsistent. Methods: We utilized 1,043 CRC cases and their 1,627 unaffected sibling controls obtained from the Colon Cancer Family Registry (C-CFR). Individuals were genotyped for twelve TGFBR1 haplotype tagging SNPs. SNPs associated with CRC risk were validated in 261 CRC cases and 531 controls of African American ancestry and 990 CRC cases and 3,427 controls of Han Chinese ancestry. Validated SNPs were functionally characterized with respect to TGFBR1 expression and TGF-β signaling. Results: The TGFBR1 rs7034462-TT genotype was associated with CRC risk in C-CFR participants (OR 3.80[1.46-9.85]) and African Americans (OR 8.16[2.07-32.08]) (see Table). The TT genotype was associated with stage III and stage IV at diagnosis in C-CFR participants (OR 2.99[1.15-7.81] and OR 9.38[1.54-57.28]) and African Americans (OR 5.89[1.15-30.02] and OR 12.75[1.88-86.33]), respectively. The rs7034462-CT genotype was associated with decreased risk for CRC in African Americans (OR 0.55[0.31-0.99]) and Han Chinese (OR 0.67[0.48-0.95]) (see table). Cells carrying the rs7034462-TT genotype exhibited decreased constitutive TGFBR1 expression, increased SMAD7 expression, and decreased TGF-β signaling. Conclusions: The TGFBR1 rs7034462-T allele has dual, opposite roles with respect to CRC risk. The rare rs7034462-TT genotype is a moderate penetrance genotype associated with risk for CRC and advanced stage disease at diagnosis. In contrast, the common rs7034462-CT genotype is associated with decreased CRC risk. [Table: see text]

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.