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In 2007 the Cancer Care Ontario Hepatobiliary-Pancreatic (HPB) Community of Practice was formed during the wake of provincial regionalization of HPB services in Ontario, Canada. Despite being conceptualized within the literature as an educational intervention, communities of practice (CoP) are increasingly being adopted in healthcare as quality improvement initiatives. A qualitative case study approach using in-depth interviews and document analysis was employed to gain insight into the perceptions and attitudes of the HPB surgeons in the CoP. This study demonstrates how an engineered formal or idealized structure of a CoP was created in tension with the natural CoPs that HPB surgeons identified with during and after their training. This tension contributed to the inactive and/or marginal participation by some of the surgeons in the CoP. The findings of this study represent a cautionary tale for such future engineering attempts in two distinct ways: (1) a CoP in surgery cannot simply be created by regulatory agencies, rather they need to be supported in a way to evolve naturally, and (2) when the concept of CoPs is co-opted by governing bodies, it does not necessarily capture the power and potential of situated learning. To ensure CoP sustainability and effectiveness, we suggest that both core and peripheral members need to be more directly involved at the inception of the COP in terms of design, organization, implementation and ongoing management.

Background: People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers.Methods: This study included 1966 (56% female) carriers of an MMR gene mutation (719 MLH1, 931 MSH2, 211 MSH6 and 105 PMS2) who were recruited from the USA, Canada, Australia and New Zealand into the Colon Cancer Family Registry between 1997 and 2012. Information on lifestyle factors including supplement intake was collected at the time of recruitment. Using Cox proportional hazards regression weighted to correct for ascertainment bias, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between self-reported multivitamin, calcium and folic acid supplement intake and CRC risk.Results: Of 744 carriers with CRC, 18%, 6% and 5% reported intake of multivitamin, calcium and folic acid supplements for at least 1 month, respectively, compared with 27%, 11% and 10% of 1222 carriers without CRC. After adjusting for identified confounding variables, a decreased CRC risk was associated with multivitam inintake for at least 3 years (HR 0.47, 95% CI 0.32-0.69) and calcium intake for at least 3 years(HR 0.42, 95% CI 0.23-0.74), compared with never users. There was no evidence of an association between folic acid supplement intake and CRC risk (P = 0.82).Conclusion: Intake of multivitamin and calcium supplements might be associated with a decreased risk of CRC for MMR gene mutation carriers. [ABSTRACT FROM AUTHOR]

Diet and lifestyle influence colorectal cancer (CRC) risk but the molecular events that mediate these effects are poorly characterized. Several dietary and lifestyle factors can modulate DNA methylation suggesting that they may influence CRC risk through epigenetic regulation of cancer-related genes. The Wnt regulatory genes DKK1 and Wnt5a are important contributors to colonic carcinogenesis and are often silenced by promoter hypermethylation in CRC; however, the dietary contributions to these events have not been explored. To investigate the link between dietary/lifestyle factors and epigenetic regulation of these Wnt signaling genes, we assessed promoter methylation of these genes in a large cohort of Canadian CRC patients from Ontario (n = 549) and Newfoundland (n = 443) and examined associations to dietary/lifestyle factors implicated in CRC risk and/or DNA methylation including intake of vitamins, fats, cholesterol, fiber, and alcohol as well as body mass index (BMI), and smoking status. Several factors were associated with methylation status including alcohol intake, BMI, and cigarette smoking. Most significantly, however, dietary vitamin D intake was strongly negatively associated with DKK1 methylation in Newfoundland (P = 0.001) and a similar trend was observed in Ontario. These results suggest that vitamin D and other dietary/lifestyle factors may alter CRC risk by mediating extracellular Wnt inhibition. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Living donor liver transplantation (LDLT) is an attractive option for patients with unresectable, bilobar colorectal liver metastases (CRLM). However, it is not available in most centers beyond study protocols. This study describes the interim experience with LDLT for CRLM at a large North American transplant and hepatobiliary center. f STUDY DESIGN: Adults with unresectable CRLM, receiving systemic chemotherapy, were recruited into a prospective clinical trial. Data on demographics, referral patterns, and clinical characteristics were extracted from October 2016 to February 2023. Patients were divided into 3 groups: transplanted, resected, and control (excluded with continuation of systemic chemotherapy). Overall survival and recurrence-free survival were compared. RESULTS: Eighty-one referred patients were assessed for LDLT: 7 received transplants, 22 underwent resection, and 48 were controls. All had similar preassessment baseline characteristics. Median time from initial assessment to transplantation was 15.4 months. The control population had significantly worse postassessment overall survival than the transplanted population (p = 0.002) and resected population (p < 0.001). The median postoperative follow-up duration was 21.4 months (resection) and 14.8 months (LDLT). There was no difference in overall survival between the transplanted and resected populations (1-year 100% vs 93.8%; 3-year 100% vs 43.3%, p = 0.17). However, recurrence-free survival was superior in the LDLT group (1-year 85.7% vs 11.4%; 3-year 68.6% vs 11.4%, p = 0.012). CONCLUSIONS: Most patients with unresectable CRLM referred for LDLT are deemed ineligible for trial inclusion. However, the excellent oncologic outcomes in patients who meet criteria for LDLT supports its role in highly selected populations. Future results after the trial's completion will inform long-term outcomes. [ABSTRACT FROM AUTHOR]

Objectives: In resectable pancreatic ductal adenocarcinoma (PDAC), few pre-operative prognostic biomarkers are available. Radiomics has demonstrated potential but lacks external validation. We aimed to develop and externally validate a pre-operative clinical-radiomic prognostic model., Methods: Retrospective international, multi-center study in resectable PDAC. The training cohort included 352 patients (pre-operative CTs from five Canadian hospitals). Cox models incorporated (a) pre-operative clinical variables (clinical), (b) clinical plus CT-radiomics, and (c) post-operative TNM model, which served as the reference. Outcomes were overall (OS)/disease-free survival (DFS). Models were assessed in the validation cohort from Ireland (n = 215, CTs from 34 hospitals), using C-statistic, calibration, and decision curve analyses., Results: The radiomic signature was predictive of OS/DFS in the validation cohort, with adjusted hazard ratios (HR) 2.87 (95% CI: 1.40-5.87, p < 0.001)/5.28 (95% CI 2.35-11.86, p < 0.001), respectively, along with age 1.02 (1.01-1.04, p = 0.01)/1.02 (1.00-1.04, p = 0.03). In the validation cohort, median OS was 22.9/37 months (p = 0.0092) and DFS 14.2/29.8 (p = 0.0023) for high-/low-risk groups and calibration was moderate (mean absolute errors 7%/13% for OS at 3/5 years). The clinical-radiomic model discrimination (C = 0.545, 95%: 0.543-0.546) was higher than the clinical model alone (C = 0.497, 95% CI 0.496-0.499, p < 0.001) or TNM (C = 0.525, 95% CI: 0.524-0.526, p < 0.001). Despite superior net benefit compared to the clinical model, the clinical-radiomic model was not clinically useful for most threshold probabilities., Conclusion: A multi-institutional pre-operative clinical-radiomic model for resectable PDAC prognostication demonstrated superior net benefit compared to a clinical model but limited clinical utility at external validation. This reflects inherent limitations of radiomics for PDAC prognostication, when deployed in real-world settings., Key Points: • At external validation, a pre-operative clinical-radiomics prognostic model for pancreatic ductal adenocarcinoma (PDAC) outperformed pre-operative clinical variables alone or pathological TNM staging. • Discrimination and clinical utility of the clinical-radiomic model for treatment decisions remained low, likely due to heterogeneity of CT acquisition parameters. • Despite small improvements, prognosis in PDAC using state-of-the-art radiomics methodology remains challenging, mostly owing to its low discriminative ability. Future research should focus on standardization of CT protocols and acquisition parameters., (© 2021. European Society of Radiology.)

Competing Interests: Competing interests: Grainne O’Kane received consultant fees and honoraria from AstraZeneca, Roche and Eisai outside of the submitted work. No other competing interests were declared.

Background: Positron emission tomography (PET), alone or combined with computed tomography (CT), potentially enhances detection of occult metastatic colorectal cancer., Methods: We compared the impact of PET/PET-CT with conventional imaging, versus conventional imaging alone, in patients with potentially resectable colorectal cancer liver metastases. MEDLINE, EMBASE, and CENTRAL were searched for studies investigating PET/PET-CT to determine resectability. Outcomes included overall (OS), disease-free survival (DFS), change in surgical management, and futile laparotomy. Evidence quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. A pre-specified protocol was registered in PROSPERO., Results: Of 4034 articles, two randomized trials (n = 554), and 11 non-randomized studies (n = 2251) were included. PET/PET-CT did not improve OS (hazard ratio [HR] 0.94, 95% CI 0.69-1.26, moderate quality) or DFS (HR 1.01, 95% CI 0.82-1.26, moderate quality). In the two trials, PET/PET-CT changed surgical management in 8% of cases (95% CI 5-11%, high quality), and did not significantly reduce futile laparotomies (risk ratio 0.59, 95% CI 0.24-1.47, low quality). Among non-randomized studies, PET/PET-CT changed surgical management in 20% of cases (95% CI 17-22%, very low quality) and reduced futile laparotomies (odds ratio 0.51, 95% CI 0.32-0.81, very low quality)., Conclusions: Moderate-quality evidence suggests that preoperative PET/PET-CT does not improve OS or DFS in patients with colorectal cancer liver metastases. These results do not support routine use of PET/PET-CT in patients with potentially resectable disease. The main limitation of this study was the lack of randomized studies., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age-specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3-13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9-10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0-46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome., (© 2015 UICC.)

Background: The treatment of colorectal cancer in young patients involves both management of the incident cancer and consideration of the possibility of Lynch syndrome and the development of metachronous colorectal cancers., Objective: This study aims to assess the prognostic role of DNA mismatch repair deficiency and extended colorectal resection for metachronous colorectal neoplasia risk in young patients with colorectal cancer., Design, Setting, and Patients: This is a retrospective review of 285 patients identified in our GI cancer registry with colorectal cancer diagnosed at 35 years or younger in the absence of polyposis., Main Outcome Measures: Using univariate and multivariate analysis, we assessed the prognostic role of mismatch repair deficiency and standard clinicopathologic characteristics, including the extent of resection, on the rate of developing metachronous colorectal neoplasia requiring resection., Results: Mismatch repair deficiency was identified in biospecimens from 44% of patients and was significantly associated with an increased risk for metachronous colorectal neoplasia requiring resection (10-year cumulative risk, 13.5% ± 4.2%) compared with 56% of patients with mismatch repair-intact colorectal cancer (10-year cumulative risk, 5.8% ± 3.3%; p = 0.011). In multivariate analysis, mismatch repair deficiency was associated with a HR of 3.65 (95% CI, 1.44-9.21; p = 0.006) for metachronous colorectal neoplasia, whereas extended resection with ileorectal or ileosigmoid anastomosis significantly decreased the risk of metachronous colorectal neoplasia (HR, 0.21; 95% CI, 0.05-0.90; p = 0.036)., Limitations: This study had a retrospective design, and, therefore, recommendations for colorectal cancer surgery and screening were not fully standardized. Quality of life after colorectal cancer surgery was not assessed., Conclusions: Young patients with colorectal cancer with molecular hallmarks of Lynch syndrome were at significantly higher risk for the development of subsequent colorectal neoplasia. This risk was significantly reduced in those who underwent extended resection compared with segmental resection.

Importance: Li-Fraumeni syndrome, usually characterized by germline TP53 mutations, is associated with markedly elevated lifetime risks of multiple cancers, and has been linked to an increased risk of early-onset colorectal cancer., Objective: To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer., Design, Setting, and Participants: This was a multicenter cross-sectional cohort study of individuals recruited to the Colon Cancer Family Registry (CCFR) from 1998 through 2007 (genetic testing data updated as of January 2015). Both population-based and clinic-based patients in the United States, Canada, Australia, and New Zealand were recruited to the CCFR. Demographic information, clinical history, and family history data were obtained at enrollment. Biospecimens were collected from consenting probands and families, including microsatellite instability and DNA mismatch repair immunohistochemistry results. A total of a 510 individuals diagnosed as having colorectal cancer at age 40 years or younger and lacking a known hereditary cancer syndrome were identified from the CCFR as being potentially eligible. Fifty-three participants were excluded owing to subsequent identification of germline mutations in DNA mismatch repair genes (n = 47) or biallelic MUTYH mutations (n = 6)., Interventions: Germline sequencing of the TP53 gene was performed. Identified TP53 alterations were assessed for pathogenicity using literature and international mutation database searches and in silico prediction models., Main Outcomes and Measures: Frequency of nonsynonymous germline TP53 alterations., Results: Among 457 eligible participants (314, population-based; 143, clinic-based; median age at diagnosis, 36 years [range, 15-40 years]), 6 (1.3%; 95% CI, 0.5%-2.8%) carried germline missense TP53 alterations, none of whom met clinical criteria for Li-Fraumeni syndrome. Four of the identified TP53 alterations have been previously described in the literature in probands with clinical features of Li-Fraumeni syndrome, and 2 were novel alterations., Conclusions and Relevance: In a large cohort of patients with early-onset colorectal cancer, germline TP53 mutations were detected at a frequency comparable with the published prevalence of germline APC mutations in colorectal cancer. With the increasing use of multigene next-generation sequencing panels in hereditary cancer risk assessment, clinicians will be faced with the challenge of interpreting the biologic and clinical significance of germline TP53 mutations in families whose phenotypes are atypical for Li-Fraumeni syndrome.

Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (≥40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma.

Background: Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability., Objective: We assessed the differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences., Design: This is a population-based prospective cohort study for cancer survival., Settings: This study was conducted within the Colon Cancer Family Registry, an international consortium. Participants were identified from population-based cancer registries in the United States, Canada, and Australia., Patients: Information on tumor site, microsatellite instability, and survival after diagnosis was available for 3284 men and women diagnosed with incident invasive colon or rectal cancer between 1997 and 2002, with ages at diagnosis ranging from 18 to 74., Main Outcome Measures: Cox regression was used to calculate hazard ratios for the association between all-cause mortality and tumor location, overall and by microsatellite instability status., Results: Distal colon (HR, 0.59; 95% CI, 0.49-0.71) and rectal cancers (HR, 0.68; 95% CI, 0.57-0.81) were associated with lower mortality than proximal colon cancer overall. Compared specifically with patients with proximal colon cancer exhibiting no/low microsatellite instability, patients with distal colon and rectal cancers experienced lower mortality, regardless of microsatellite instability status; patients with proximal colon cancer exhibiting high microsatellite instability had the lowest mortality., Limitations: Study limitations include the absence of stage at diagnosis and cause-of-death information for all but a subset of study participants. Some patient groups defined jointly by tumor site and microsatellite instability status are subject to small numbers., Conclusion: Proximal colon cancer survival differs from survival for distal colon and rectal cancer in a manner apparently dependent on microsatellite instability status. These findings support the premise that proximal colon, distal colon, and rectal cancers are clinicopathologically distinct.

Introduction: The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis., Methods: To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia., Results: The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P=0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR=2.8; 95%CI: 1.2-6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer., Discussion: This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers., Methods: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population., Results: Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97)., Conclusion: Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.

Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer death., Methods: A prospective cohort study was undertaken between 2003 and 2011 at a tertiary care centre in Toronto, Canada. Two hundred and sixty-two subjects were enrolled based on an elevated estimated lifetime risk for pancreatic cancer due to known genetic mutations and/or cancer family history. Subjects underwent annual magnetic resonance imaging, followed by additional investigations if abnormal findings were detected. Evidence of malignancy or suspicious macroscopic abnormalities prompted referral for surgical intervention., Results: Average length of follow-up was 4.2 years, during which 84/262 (32%) subjects demonstrated pancreatic abnormalities. Three participants developed pancreatic adenocarcinoma (one 1.5-cm tumor was resected but recurred, while the other two subjects developed metastatic cancer), and a fourth participant developed a pancreatic neuroendocrine tumor that was resected. Fifteen subjects had radiologic evidence of branch-duct intraductal papillary mucinous neoplasms, of which two underwent surgical resection. Sixty-five subjects had simple pancreatic cysts that have remained stable., Conclusion: Magnetic resonance imaging can detect small pancreatic tumors and cystic lesions, but further improvement in sensitivity is needed. An understanding of the natural history of pre-invasive lesions in members of high-risk families is necessary for developing a more effective screening program.

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers., (Copyright © 2010 UICC.)

Background: Genome-wide association studies (GWAS) have led to the identification of a number of common susceptibility loci for colorectal cancer (CRC); however, none of these GWAS have considered gene-environment (G × E) interactions. Therefore, it is unclear whether current hits are modified by environmental exposures or whether there are additional hits whose effects are dependent on environmental exposures., Methods: We conducted a systematic search for G × E interactions using genome wide data from the Colon Cancer Family Registry that included 1,191 cases of microsatellite stable (MSS) or microsatellite instability-low (MSI-L) CRC and 999 controls genotyped using either the Illumina Human1M or Human1M-Duo BeadChip. We tested for interactions between genotypes and 14 environmental factors using 3 methods: a traditional case-control test, a case-only test, and the recently proposed 2-step method by Murcray and colleagues. All potentially significant findings were replicated in the ARCTIC Study., Results: No G × E interactions were identified that reached genome-wide significance by any of the 3 methods. When analyzing previously reported susceptibility loci, 7 significant G × E interactions were found at a 5% significance level. We investigated these 7 interactions in an independent sample and none of the interactions were replicated., Conclusions: Identifying G × E interactions will present challenges in a GWAS setting. Our power calculations illustrate the need for larger sample sizes; however, as CRC is a heterogeneous disease, a tradeoff between increasing sample size and heterogeneity needs to be considered., Impact: The results from this first genome-wide analysis of G × E in CRC identify several challenges, which may be addressed by large consortium efforts., (©2011 AACR.)

Background & Aims: The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene., Methods: A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification., Results: Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5-132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P=.01), had a higher proportion of right-sided (P=.01), synchronous cancers (P<.01), and personal history of adenomatous polyps (P=.003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02-2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P=.02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction<.001)., Conclusions: Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways.

Overweight and obesity are linked with several chronic diseases, including colorectal cancer, among men, but results among women are equivocal. Previous evidence suggests that menopausal status, postmenopausal hormone use, and family history of cancer may modify the link between adiposity and colorectal cancer. In data from two population-based case-control studies (cases: 1,292 males and 1,404 females; controls: 1,465 males and 1,203 females) in Ontario and Newfoundland, Canada, we examined the link between colorectal cancer and body mass index (BMI) at two reference periods (BMI 2 years prior and BMI at age 20 years), weight gain since age 20 years, and height. Based on recent BMI indices among men, obesity (BMI >/=30 kg/m(2)) was associated with an 80% [95% confidence interval (95% CI), 1.43-2.27] increased risk of colorectal cancer relative to a normal BMI (18.5-24.9 kg/m(2)). The same comparison for BMI at age 20 years suggested a 94% increased risk of colorectal cancer (95% CI, 1.19-3.16). Odds ratios were similar among subgroups of men with and without a clinically defined familial risk of cancer (according to the Amsterdam or revised Bethesda criteria for Lynch syndrome). Associations were moderately stronger for cancer of the colon than cancer of the rectum. Among women, BMI and weight gain were not linked with colorectal cancer; the null associations were persistent in subgroups of familial risk of cancer, menopausal status, estrogenic status, and subsite. Tall height (>1.75 m), however, was linked with increased risk of colorectal cancer among women (odds ratio, 2.27; 95% CI, 1.46-3.59) but not among men. This study suggests that obesity is associated with increased risk of sporadic and Lynch syndrome-related colon and rectal cancers among men but not among women, whereas height is directly linked with all such cancers among women but not among men.

Purpose: The role of menstrual and reproductive risk factors for gastric cancer has not been well studied., Methods: This population-based case-control study included 326 women aged 20 to 74 years with gastric adenocarcinoma. Controls were 326 women frequency matched on age. Data for reproductive and/or hormonal exposure and gastric cancer risk factors were captured through self-administered questionnaire., Results: Later age at menarche was associated with increased risk for adenocarcinoma compared with menarche onset at younger than 13 years of age (13 to 14 years: odds ratio [OR], 1.45; 95% confidence interval [CI], 1.00-2.10; > or =15 years: OR, 1.93; 95% CI, 1.19-3.13). Compared with premenopause, natural menopause was associated with increased risk for adenocarcinoma (OR, 1.99; 95% CI, 0.98-4.05). Compared with nulliparity, 4 or more births were associated with decreased risk for gastric cancer, as was being pregnant for 5 months or longer if the first pregnancy occurred at younger than 24 years (OR, 0.55; 95% CI, 0.31-0.96) or 25 years or older (OR, 0.67; 95% CI, 0.38-1.18). Oral contraceptives and hormone replacement therapy were associated with a non-statistically significant decreased risk., Conclusion: These findings suggest that hormonal factors associated with greater exposure to estrogen and/or progesterone may be associated with decreased risk for gastric cancer.

Purpose: The purpose of this study was to examine the health-related quality of life in a sample of Canadian adults diagnosed with familial adenomatous polyposis and desmoid tumor., Methods: The study was conducted in two parts. Seven individuals participated in a focus group prior to a mail-out survey. A cross-sectional mail-out survey was administered to eligible individuals who were actively followed at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital., Results: Forty-one individuals (25 female and 16 male) were available to be contacted by the registry coordinator and 23 questionnaire packages were completed, resulting in a 56.1 percent participation rate. The results of this study demonstrated a reduced health-related quality of life for individuals living with familial adenomatous polyposis and desmoid tumor for over 10 years. The main predictors of health-related quality of life in this analysis included marital status (married vs. not married), prior knowledge of desmoid tumor in the family, and current level of hopelessness (R(2) = 0.856, df = 13, F = 26.8, P < 0.001). The qualitative content analysis of themes from the focus group indicated that ongoing medical uncertainty and lack of information from health care professionals, isolation, and family communication were the main challenges in living with desmoid tumors., Conclusions: The findings from this study suggest that ongoing education of health care professionals is warranted and that information and support interventions may be beneficial to this clinical population.