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Jasperson KW, Samowitz WS, Burt RW. Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin. Constitutional mismatch repair-deficiency (CMMR-D) syndrome is an autosomal recessive condition characterized by hematologic malignancies, brain tumors, Lynch syndrome-associated cancers and skin manifestations reminiscent of neurofibromatosis type 1 (NF1). In contrast to Lynch syndrome, CMMR-D syndrome is exceptionally rare, onset typically occurs in infancy or early childhood and, as described in this report, may also present with colonic polyposis suggestive of attenuated familial adenomatous polyposis (AFAP) or MUTYH associated polyposis (MAP). Here we describe two sisters with CMMR-D syndrome due to germline bi-allelic MSH6 mutations. Both sisters are without cancer, are older than typical for this condition, have NF1 associated features and a colonic phenotype suspicious for an attenuated polyposis syndrome. This report highlights the role of skin examinations in leading to an underlying genetic diagnosis in individuals with colonic adenomatous polyposis, but without mutations associated with AFAP or MAP. [ABSTRACT FROM AUTHOR]

That colorectal screening rates need improvement is well-known; how to accomplish the task has been the focus of recent research. Consider easing test preparation, enlisting the support staff to order testing, and, of course, increasing patient education. [ABSTRACT FROM AUTHOR]

Background and Aims: Women are at risk of colorectal cancer (CRC) during pregnancy but this fact is underappreciated. We performed a population-based study to evaluate the rate, predictors, and familial risk for pregnancy associated CRC in Utah., Methods: All newly diagnosed cases of CRC between 1973 and 2014 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database., Results: Of the 12,886 females diagnosed with CRC, 73 were diagnosed with CRC (0.57%) during the period of obstetric delivery/childbirth. Pregnancy associated CRC was diagnosed at a mean age of 31.9 years, and cancers were less frequently located in the proximal colon compared with women with non-pregnancy associated CRC. First-degree relatives of cases with pregnancy associated CRC had a nearly threefold higher risk of CRC (OR, 2.76; 95% CI, 1.26-6.01) compared with relatives of CRC-free individuals., Conclusions: Of women diagnosed with CRC, less than 1% were diagnosed during or soon after obstetric delivery/childbirth. Relatives of these patients have a nearly threefold greater risk of CRC than those without a family history of CRC. These results provide physicians with data to guide the care of patients and their relatives with pregnancy associated CRC.

Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Pancreas adenocarcinoma (PC) has an undefined hereditary component. We quantified the familial risk of PC among relatives of patients diagnosed with PC and stratified it based on anatomic location of PC and age and sex of the proband., Methods: This is a retrospective, population-based, case-control study of PC diagnosed in Utah between 1980 and 2011. The Utah population database and cancer registry were used to identify index patients with PC. The risk of PC in first-degree relatives (FDRs), second-degree relatives (SDRs), and first cousins (FCs) of probands was compared with randomly selected sex- and age-matched population controls., Results: A total of 4,095 patients and 40,933 controls were identified. The relative risk (RR) of PC was 1.76 (95% CI 1.35-2.29) in FDRs, 1.42 (95% CI 1.18-1.7) in SDRs and 1.08 (95% CI 0.95-1.23) in FCs of probands compared to relatives of PC-free controls. The RR were elevated in FDRs (1.96, 95% CI 1.45-2.65), SDRs (1.54, 95% CI 1.19-1.98) and FCs (1.18, 95% CI 1.0-1.64) of female probands. Among probands diagnosed as < 65 years, RR was 2.12 (95% CI 1.37-3.28) in FDRs, 1.94 (95% CI 1.44-2.62) in SDRs, and 1.28 (95% CI 1.0-1.64) in FCs. Overall, the RR for PC was elevated in FDRs regardless of the anatomic location of PC., Discussion: There is an increased risk of PC in FDR and more distant relatives of patients with PC. Relatives of female patients with PC and patients diagnosed at age < 65 years are at a significantly increased risk of PC.

Background & Aims: Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6-60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy)., Methods: Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC. Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n = 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC., Results: Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P = .016) and were of an early stage (86% vs 69%; P = .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P = .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58-11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs., Conclusion: In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing colorectal cancer (CRC). Although family history of CRC is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of CRC in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR)., Methods: We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. CRCs were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. CRC incidence was compared with that of the state population by standardized incidence ratios (SIRs)., Results: A cohort of 9505 individuals with IBD was identified and 101 developed CRC during the study period. The SIR for CRC in patients with Crohn's disease was 3.4 (95% CI, 2.3-4.4), and in patients with ulcerative colitis was 5.2 (95% CI, 3.9-6.6). Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had the greatest risk of CRC (SIR, 14.8; 95% CI, 8.3-21.2). A history of CRC in a FDR was associated with a nearly 8-fold increase in risk of CRC in patients with IBD (SIR, 7.9; 95% CI, 1.6-14.3), compared with the state population., Conclusions: Patients with IBD have a 3- to 5-fold increase in risk of CRC, and those with CRC in a FDR have an almost 8-fold increase in risk. Family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Sessile serrated adenoma/polyps (SSA/Ps) of the colon account for 20-30% of all colon cancers. Small non-coding RNAs, including microRNAs (miRNAs), may function as oncogenes or tumor suppressor genes involved in cancer development. Small RNA sequencing (RNA-seq) was used to characterize miRNA profiles in SSA/Ps, hyperplastic polyps (HPs), adenomatous polyps and paired uninvolved colon. Our 108 small RNA-seq samples' results were compared to small RNA-seq data from 212 colon cancers from the Cancer Genome Atlas. Twenty-three and six miRNAs were differentially expressed in SSA/Ps compared to paired uninvolved colon and HPs, respectively. Differential expression of MIR31-5p, MIR135B-5p and MIR378A-5p was confirmed by RT-qPCR. SSA/P-specific miRNAs are similarly expressed in colon cancers containing genomic aberrations described in serrated cancers. Correlation of miRNA expression with consensus molecular subtypes suggests more than one subtype is associated with the serrated neoplasia pathway. Canonical pathway analysis suggests many of these miRNAs target growth factor signaling pathways., (© 2018 Wiley Periodicals, Inc.)

Maintaining mechanical circulatory support (MCS) device patients in a specified therapeutic range for anticoagulation remains challenging. Subtherapeutic international normalized ratios (INRs) occur frequently while on warfarin therapy. An effective anticoagulant bridge strategy may improve the care of these patients. This retrospective review of MCS patients with subtherapeutic INRs compared an intravenous unfractionated heparin (UFH) strategy with a subcutaneous enoxaparin or fondaparinux strategy. Native thromboelastography (n-TEG) was used to evaluate anticoagulant effect with coagulation index (CI) as the primary outcome measure. Enoxaparin 0.5 mg/kg subcutaneously (SC) every 12 hours or fondaparinux 2.5-5 mg SC daily were compared with an initial UFH rate of 5 units/kg/hr and titrated to stated n-TEG goal range. The anticoagulant groups UFH, enoxaparin, and fondaparinux were found to be statistically similar with regard to frequency in n-TEG goal range, above range (hypercoagulability), or below range (hypocoagulability). Clinical outcomes were similar among groups with three gastrointestinal bleeds in UFH, one in enoxaparin, and one in fondaparinux groups. Device thrombosis occurred in one UFH patient, while UFH and fondaparinux groups had one ischemic cerebrovascular accident event each. These strategies provided comparable n-TEG results and clinical outcomes when compared with intravenous UFH. Low-dose enoxaparin or fondaparinux may provide an alternative anticoagulant bridging option in MCS patients presenting with subtherapeutic INR.

Background: Patients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk-reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance., Methods: Individuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number., Results: The distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype., Conclusions: Most FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location., Trial Registration: NCT 01187901 registered August 24, 2010, prospective to enrollment.

Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial., Objective: To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP., Design, Setting, and Participants: Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah., Interventions: Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months., Main Outcomes and Measurements: The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment., Results: Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009)., Conclusion and Relevance: In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum., Trial Registration: clinicaltrials.gov Identifier: NCT01187901.

Background: Sessile serrated polyps (SSPs) have emerged as important precursors for a large number of sporadic colorectal cancers. They are difficult to detect during colonoscopy due to their flat shape and the excessive amounts of secreted mucin that cover the polyps. The underlying genetic and epigenetic basis for the emergence of SSPs is largely unknown with existing genetic studies confined to a limited number of oncogenes and tumor suppressors. A full characterization of the genetic and epigenetic landscape of SSPs would provide insight into their origin and potentially offer new biomarkers useful for detection of SSPs in stool samples., Methods: We used a combination of genome-wide mutation detection, exome sequencing and DNA methylation profiling (via methyl-array and whole-genome bisulfite sequencing) to analyze multiple samples of sessile serrated polyps and compared these to familial adenomatous polyps., Results: Our analysis revealed BRAF-V600E as the sole recurring somatic mutation in SSPs with no additional major genetic mutations detected. The occurrence of BRAF-V600E was coincident with a unique DNA methylation pattern revealing a set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples. These methylation patterns effectively distinguished sessile serrated polys from adenomatous polyps and did so more effectively than parallel gene expression profiles., Conclusions: This study provides an important example of a single oncogenic mutation leading to reproducible global DNA methylation changes. These methylated markers are specific to SSPs and could be of important clinical relevance for the early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.

To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months ( P < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4-15. ©2017 AACR See related editorial by Shureiqi, p. 1 ., (©2017 American Association for Cancer Research.)

Importance: The data describing cancer risks associated with Lynch syndrome are variable., Objectives: To quantify the prevalence of families that fulfill the Amsterdam I or II criteria for Lynch syndrome in the Utah population and investigate the risk of colonic and extracolonic cancers in family members and their relatives., Design, Setting, and Participants: In a population-based study, 202 families with Amsterdam I and II criteria–positive pedigrees in the Utah Population Database were identified. Of these, all cancer diagnoses in members of families with Amsterdam criteria and their first-degree, second-degree, and first-cousin relatives were located through linkage to the Utah Cancer Registry. The study was conducted from May 1 to June 30, 2016., Main Outcomes and Measures: Standardized morbidity ratios (SMRs) were estimated by comparing the observed rates of cancer in relatives with population-expected rates estimated internally from the Utah Population Database., Results: A total of 202 families meeting Amsterdam criteria for Lynch syndrome accounted for 2.6% of all colorectal cancers in the state; of these, 59 met both the Amsterdam I and Amsterdam II criteria. Cancers observed in significant excess in the first-degree relatives of Amsterdam criteria pedigrees included colorectal (SMR, 10.10; 95% CI, 9.43-10.81), endometrial (SMR, 5.89; 95% CI, 5.09-6.78), stomach (SMR, 2.90; 95% CI, 2.02-4.03), small intestine (SMR, 7.72; 95% CI, 5.17-11.08), prostate (SMR, 1.94; 95% CI, 1.73-2.17), kidney (SMR, 3.22; 95% CI, 2.45-4.16), urinary bladder (SMR, 1.62; 95% CI, 1.22-2.12), thyroid (SMR, 2.26; 95% CI, 1.55-3.17), and non-Hodgkin lymphoma (SMR, 2.10; 95% CI, 1.64-2.65). Risks of colorectal and endometrial cancers were also found to be elevated in second-degree (SMR, 4.31; 95% CI, 3.98-4.65 and SMR, 2.70; 95% CI, 2.30-3.14, respectively) and first-cousin (SMR, 1.85; 95% CI, 1.70-2.00 and SMR, 1.50; 95% CI, 1.29-1.73, respectively) relatives of families with Amsterdam criteria., Conclusions and Relevance: In this population-based study of cancer risk in families fulfilling the Amsterdam criteria, many of the cancers previously reported to be associated with Lynch syndrome were observed, several previously unreported cancer associations were noted, and the risk of colorectal and endometrial cancer were markedly increased in first-, second-, and even third-degree relatives of these families. This study provides clinicians with population-based, unbiased data to counsel members of families meeting the Amsterdam criteria regarding their elevated risks of cancer and the importance of cancer screening.

Objectives: Colonoscopy is widely recommended for colorectal cancer (CRC) screening, but evidence to guide the optimal frequency of repeat screening examination is limited. We examined the duration and magnitude of the risk of developing CRC, following a negative colonoscopy in those at average risk and those with a first-degree family history of CRC., Methods: A cohort of Utah residents aged 50-80 years who had a negative colonoscopy between 1 January 2001 and 31 December 2011 was identified using the Utah Population Database. Patients were followed from the time of the index colonoscopy until diagnosis of CRC, death, migration out of state, repeat colonoscopy, or end of the study period. CRC incidence after the index colonoscopy was compared with that of the state population by standardized incidence ratios (SIRs)., Results: A cohort of 131,349 individuals at average risk with a negative colonoscopy was identified. Compared with the state population, a negative colonoscopy was associated with SIRs of 0.15 (95% confidence interval (CI): 0.08-0.23) at 1 year, 0.26 (95% CI: 0.19-0.32) at 2-5 years, 0.33 (95% CI: 0.22-0.43) at 5-6 years, and 0.60 (95% CI: 0.44-0.76) at 7-10 years for CRC following the index colonoscopy. In a secondary analysis involving only patients with a first-degree relative with CRC, patients had a significantly lower incidence of CRC only for the first 5 years of follow-up (SIR 0.39, 95% CI: 013-0.64). There was also a difference in the risk of proximal (SIR 0.72, 95% CI: 0.45-0.98) and distal (SIR 0.51, 95% CI: 0.30-0.72) colon cancers at 7-10 years following a negative colonoscopy., Conclusions: The risk of developing CRC remains decreased for at least 10 years following the performance of a negative colonoscopy. However, the lower incidence of CRC in those with a family history of CRC differed in magnitude and timing being limited primarily to the first 5 years of follow-up and of lesser magnitude than that in the overall cohort.

Goals: To further characterize the gastrointestinal manifestations of Cowden syndrome in clinically well-annotated patients to improve the diagnosis of this syndrome., Background: The gastrointestinal manifestations of Cowden Syndrome, an important heritable and multiorgan cancer syndrome, are not well defined. Proper diagnosis is essential for effective cancer surveillance and prevention in these patients., Study: Cowden patients with gastrointestinal polyps were selected for medical record and pathologic slide review., Results: Of 19 total patients, genetic testing revealed pathogenic PTEN mutations in 12. Pan-colonic (11-patients, 58%) and pan-gastrointestinal (8-patients, 42%) polyp distributions were common. Inflammatory (juvenile) polyps were the most common of the hamartomatous polyp (18 patients, 95%), along with expansive lymphoid follicle polyps (12 patients, 63%), ganglioneuromatous polyps (10 patients, 53%), and intramucosal lipomas (5 patients, 26%). The findings of 2 or more hamartomatous polyp types per patient emerged as a newly described and highly prevalent (79%) feature of Cowden syndrome. Ganglioneuromatous polyps, rare in the general population, and intramucosal lipomas, which may be unique to Cowden syndrome, should both prompt further evaluation. Colonic adenomas and adenocarcinomas were common; 10 patients (53%) had single and 3 (16%) had ≥3 adenomas, whereas 2 (11%) had colonic adenocarcinoma, strengthening the emerging association of colorectal cancer with Cowden syndrome., Conclusions: The clinical phenotypes and gastrointestinal manifestations in Cowden syndrome are quite variable but this series adds the following new considerations for this syndromic diagnosis: multiple gastrointestinal hamartomas, especially 2 or more hamartoma types, and any intramucosal lipomas or ganglioneuromas. These features should warrant consideration of Cowden syndrome.

Background and Aims: The molecular, endoscopic, and histological features of IBD-associated CRC differ from sporadic CRC. The objective of this study was to describe the prevalence, clinical features, and prognosis of IBD-associated CRC compared to patients with sporadic CRC in a US statewide population-based cohort., Methods: All newly diagnosed cases of CRC between 1996 and 2011 were obtained from Utah Cancer Registry. IBD was identified using a previously validated algorithm, from statewide databases of Intermountain Healthcare, University of Utah Health Sciences, and the Utah Population Database. Logistic regression was performed to identify risk factors associated with IBD-associated cancer and Cox regression for differences in survival., Results: Among 12,578 patients diagnosed with CRC, 101 (0.8%) had a prior history of IBD (61 ulcerative colitis and 40 Crohn's disease). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (67.1 vs 52.8 years, P < 0.001). Individuals with IBD-associated CRC were more likely to be men (odds ratio [OR] 1.90, 95% CI 1.23-2.92), aged less than 65 years (OR 6.77, 95% CI 4.06-11.27), and have CRC located in the proximal colon (OR 2.79, 95% CI 1.85-4.20) than those with sporadic CRC. Nearly 20% of the IBD-associated CRCs had evidence of primary sclerosing cholangitis. After adjustment for age, gender, and stage at diagnosis, the excess hazard of death after CRC diagnosis was 1.7 times higher in IBD than in non-IBD patients (95% CI 1.27-2.33)., Conclusions: The features of patients with CRC and IBD differ significantly from those without IBD and may be associated with increased mortality.

Background: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC) and an evolving management approach. The aims of this study were to assess the polyp burden reduction over time, and the incidence of CRC in serrated polyposis patients undergoing community surveillance., Methods: This is an observational study based on prospectively collected data. A total of 96 SPS patients with no personal history of CRC were prospectively enrolled in a surveillance program under the guidance of a tertiary center. Patients underwent surveillance colonoscopy in multiple centres across New Zealand., Results: Patients underwent a median of four colonoscopies with a median interval of 15 months over a median follow-up period of 4.8 years. Five of 96 patients (5%) were referred for surgery, and the remaining 91 were managed by colonoscopy alone. In patients referred for surgery, 92% of the surveillance intervals to the fourth colonoscopy had been ≤12 months compared to 33% (P<0.001) in the colonoscopy only group, and all five (100%) had ≥20 pancolonic polyps after four procedures compared with only 5/91 (5%) in those managed by colonoscopy alone. In patients successfully managed by colonoscopy, 86% had <10 pancolonic polyps, >75% no longer had polyps ≥10mm and >90% no longer had proximal serrated polyps ≥10mm after the fourth colonoscopy. No patients were found to develop CRC during the study time period., Conclusions: Patients with SPS were managed by proactive surveillance colonoscopy in wider hospital settings under tertiary centre guidance, with only 5% requiring surgical management. No CRC was diagnosed in any patient during surveillance., Competing Interests: Dr Burt reports personal fees from Thetis Pharma outside the submitted work.

Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity. We treated VDR null mice with the carcinogen azoxymethane (AOM) and generated mice bearing a mutated APC (hypomorph) on a VDR null background (Apc1638N/+Vdr-/-). VDR null mice do not develop GI or extra-colonic tumors but loss of VDR decreased intestinal tumor latency and increased progression to adenocarcinoma in both models. AOM treatment of VDR null mice also caused squamous cell carcinoma of the anus. Although levels and distribution of total or activated β-catenin in the epithelial component of tumors were unaffected by loss of VDR, β-catenin dependent cyclin D1 expression was affected suggesting a direct VDR effect on β-catenin co-activator activity. Extra-colonic mucosa manifestations in Apc1638N/+Vdr-/- animals included increased nuclear β-catenin in submucosal stromal cells, spleno- and cardiomegaly and large epidermoid cysts characteristic of the FAP variant, Gardner's syndrome. Consistent with this, SNPs in the VDR, vitamin D binding protein and CYP24 as well as mutations in APC distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner's syndrome, as well as in the etiology of anal cancer.

Background and Objectives: Biliary tract cancers (BTC) including, cholangiocarcinoma (CC) and gallbladder cancer (GBC), are rare and highly fatal malignancies. The etiology and inherited susceptibility of both malignancies are poorly understood. We quantified the risk of BTC in first-degree (FDR), second-degree (SDR), and first cousin (FC) relatives of individuals with BTC, stratified by tumor subsite., Methods: BTC diagnosed between 1980 and 2011 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and gender-matched BTC-free controls were selected to form the comparison group for determining BTC risk in relatives using Cox regression analysis., Results: Of the 1302 index patients diagnosed with BTC, 550 (42.2 %) were located in the gallbladder and 752 (57.8 %) were cholangiocarcinomas. There was no elevated risk of BTC (all subsites combined) in FDRs (HR 0.94, 95 % CI 0.29-3.0), SDRs (HR 0.25, 95 % CI 0.06-1.03), and FCs (HR 0.96, 95 % CI 0.61-1.51) of BTC cases compared to cancer-free controls. Similarly, no increased familial risk of GBC or CC was found in relatives of BTC patients stratified by tumor subsite compared to relatives of controls., Conclusions: Relatives of BTC patients are not at an increased risk of GBC or CC in a statewide population. This suggests that biliary tract cancer risk is not associated with a familial predisposition and may be mitigated more strongly by environmental modifiers.

Persons with a family history (FH) of colorectal cancer (CRC) or adenomas that are not due to known hereditary syndromes have an increased risk for CRC. An understanding of these risks, screening recommendations, and screening behaviors can inform strategies for reducing the CRC burden in these families. A comprehensive review of the literature published within the past 10 years has been performed to assess what is known about cancer risk, screening guidelines, adherence and barriers to screening, and effective interventions in persons with an FH of CRC and to identify FH tools used to identify these individuals and inform care. Existing data show that having 1 affected first-degree relative (FDR) increases the CRC risk 2-fold, and the risk increases with multiple affected FDRs and a younger age at diagnosis. There is variability in screening recommendations across consensus guidelines. Screening adherence is <50% and is lower in persons under the age of 50 years. A provider's recommendation, multiple affected relatives, and family encouragement facilitate screening; insufficient collection of FH, low knowledge of guidelines, and poor family communication are important barriers. Effective interventions incorporate strategies for overcoming barriers, but these have not been broadly tested in clinical settings. Four strategies for reducing CRC in persons with familial risk are suggested: 1) improving the collection and utilization of the FH of cancer, 2) establishing a consensus for screening guidelines by FH, 3) enhancing provider-patient knowledge of guidelines and communication about CRC risk, and 4) encouraging survivors to promote screening within their families and partnering with existing screening programs to expand their reach to high-risk groups. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2633-2645. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Sessile serrated colon adenoma/polyps (SSA/P) are found during routine screening colonoscopy and may account for 20% to 30% of colon cancers. However, differentiating SSA/Ps from hyperplastic polyps (HP) with little risk of cancer is challenging and complementary molecular markers are needed. In addition, the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood. RNA sequencing (RNA-Seq) was performed on 21 SSA/Ps, 10 HPs, 10 adenomas, 21 uninvolved colon, and 20 control colon specimens. Differential expression and leave-one-out cross-validation methods were used to define a unique gene signature of SSA/Ps. Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify a subtype of colon cancers that may develop from SSA/Ps. A total of 1,422 differentially expressed genes were found in SSA/Ps relative to controls. Serrated polyposis syndrome (n = 12) and sporadic SSA/Ps (n = 9) exhibited almost complete (96%) gene overlap. A 51-gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability. A smaller 7-gene panel showed high sensitivity and specificity in identifying BRAF-mutant, CpG island methylator phenotype high, and MLH1-silenced colon cancers. We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway. These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway. Cancer Prev Res; 9(6); 456-65. ©2016 AACR., (©2016 American Association for Cancer Research.)

Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful., Objective: To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP., Design, Setting, and Participants: Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah., Interventions: Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months., Main Outcomes and Measures: The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden., Results: Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. [table: see text]., Conclusions and Relevance: Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT 01187901., Competing Interests: Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Samadder reports being a consultant for Cook Medical. Dr Jasperson reports being an employee of Ambry Genetics. Dr Burt reports being a consultant for Myriad Genetics and receiving personal fees from Thetis Pharmaceuticals. No other disclosures were reported.

The morphologic features of the gastrointestinal polyps in hamartomatous polyposis syndromes are poorly defined. Our aim was to better characterize the gastrointestinal hamartomas in these syndromes. A blinded review was performed regarding many histologic features for every polyp. The study included 15 Cowden syndrome, 13 Peutz-Jeghers (PJS), 12 juvenile polyposis (JuvPS) patients, and 32 cases of sporadic hamartomatous polyps. A total of 375 polyps were examined. Cowden syndrome polyps were characteristically colonic, sessile, small, without surface erosion, and showing mildly inflamed fibrotic lamina propria with smooth muscle proliferation and lymphoid follicles. They showed the least degree of cystic glands and had no thick mucin. Uncommon but specific features were ganglion cells and nerve fibers within the lamina propria and mucosal fat. PJS polyps were typically of small or large bowel origin, often exophytic, seldom eroded, with inflamed edematous and fibrotic lamina propria and dilated cystic glands filled with often thick mucin. All PJS polyps showed smooth muscle proliferation, frequently widespread. The polyps of JuvPS were typically colonic, large, exophytic, eroded, with strikingly edematous, fibrotic markedly inflamed lamina propria, cystic glands filled with frequently thick mucin, and the least degree of smooth muscle proliferation. Nonsyndromic hamartomatous polyps were similar to JuvPS polyps; however, they were more often colonic, were smaller, showed more widespread smooth muscle proliferation, and were less likely to contain thick mucin. In conclusion, we were able to define the characteristic hamartomatous polyp for each hamartomatous polyposis syndrome. Awareness to these features may aid in the diagnosis of these rare syndromes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Importance: Carcinoma of unknown primary (CUP) accounts for 3% to 5% of all cancers and is associated with poor prognosis. Familial clustering of different cancer sites with CUP is unknown and may provide information regarding etiology, as well as elevated cancer risks in relatives., Objective: To quantify the risk of cancer by site in first- and second-degree relatives and first cousins of individuals with CUP., Design, Setting, and Participants: Nested case-control study of patients who received a diagnosis of CUP between 1980 and 2010 identified from the Utah Cancer Registry. Population controls with no CUP diagnosis were sex and age matched 10:1 to patients with CUP. Data about relatives were drawn from the Utah Population Database., Main Outcomes and Measures: Familial aggregation of cancer risk in relatives of cases compared with controls using Cox regression analysis., Results: For the 4160 index patients (median [interquartile range] age, 72 [62-81] years; 47.6% male) who had received a diagnosis of CUP, first-degree relatives were at an elevated risk of CUP themselves (hazard ratio [HR], 1.35 [95% CI, 1.07-1.70]), as well as lung (HR, 1.37 [95% CI, 1.22-1.54]), pancreatic (HR, 1.28 [95% CI, 1.06-1.54]), myeloma (HR, 1.28 [95% CI, 1.01-1.62]), and non-Hodgkin lymphoma (HR, 1.16 [95% CI, >1.00-1.35]) cancers compared with controls without CUP. When the analysis was restricted to relatives of cancer-free controls, additional increased risks for colon (HR, 1.19 [95% CI, 1.06-1.33]) and bladder (HR, 1.18 [95% CI, >1.00-1.38]) cancers were observed. Second-degree relatives of patients with CUP were at a slight increased risk of lung (HR, 1.14 [95% CI, 1.03-1.26]), pancreatic (HR, 1.17 [95% CI, 1.01-1.37]), breast (HR, 1.09 [95% CI, 1.02-1.16]), melanoma (HR, 1.09 [95% CI, >1.00-1.19]), and ovarian (HR, 1.19 [95% CI, 1.02-1.39]) cancers., Conclusions and Relevance: Relatives of patients with CUP are at increased risk of CUP and several other malignant neoplasms, including lung, pancreatic, and colon cancer. The present data may suggest sites of origin for CUP and provide cancer risk information for relatives of patients with CUP that can lead to effective intervention. Relatives of patients with CUP should be aware of the elevated risks for lung, pancreatic, and colon cancer and encouraged to modify risk factors and adhere to site-specific population cancer screening.

Background & Aims: Colonoscopy is widely recommended for colorectal (CRC) screening in the United States, but evidence of effectiveness is limited. We examined whether exposure to colonoscopy decreases the odds of incident CRC and death from CRC in Utah., Methods: We performed a case-control study of Utah residents, 54 to 90 years old, who received a CRC diagnosis from 2000 through 2010 (cases). Age- and sex-matched controls with no history of CRC (controls) were selected for each case. We determined receipt of colonoscopy 6 months to 10 years before the reference date for each case and control through administrative claims data. Colonoscopy exposure was compared by using conditional logistic regression., Results: We identified 5128 cases and 20,512 controls; 741 cases (14%) and 5715 controls (28%) received a colonoscopy. Exposure to colonoscopy reduced the odds for a diagnosis of CRC; the odds ratios (ORs) were 0.41 for any CRC (95% confidence interval [CI], 0.38-0.44), 0.58 for proximal colon cancer (95% CI, 0.51-0.65), and 0.29 for distal colon or rectal cancer (95% CI, 0.25-0.33). This finding was consistent among sexes, age groups, and cancer stages. Similarly, in a subgroup analysis, colonoscopy was associated with decreased odds of death from CRC (OR, 0.33; 95% CI, 0.28-0.39) in both the proximal colon (OR, 0.43; 95% CI, 0.34-0.55) and distal colon or rectum (OR, 0.23; 95% CI, 0.18-0.30)., Conclusions: In the population of Utah, colonoscopy is associated with a large reduction in risk of new-onset CRC and death from CRC. This reduction in risk for CRC was greatest for the distal colon and rectum, with a more modest reduction for proximal colon cancer., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives., Methods: CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis., Results: Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (>80 years; HR, 1.76; 95% CI, 1.59-1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (<50 years) of individuals with early-onset CRC (<40 years; HR, 7.0; 95% CI, 2.86-17.09)., Conclusions: All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation-dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele-specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42-98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The hereditary colorectal cancer syndromes comprise a heterogeneous group of conditions with varying cancer risks, gastrointestinal polyp types, nonmalignant findings, and inheritance patterns. Although each one is unique in its own right, these syndromes often have overlapping features, making diagnoses difficult in select cases. Obtaining accurate polyp history (histologic type, number, location, and age of onset), cancer history (location, type, and age of onset), and other nonmalignant features is imperative in determining the likely disease diagnosis and thereby the appropriate genetic tests for precise diagnosis in a timely fashion. This process often necessitates collaboration among surgical oncology team members and genetic counselors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Relatives of colorectal cancer (CRC) patients are at increased risk for the disease, yet screening rates still remain low. Guided by the Extended Parallel Process Model, we examined the impact of a personalized, remote risk communication intervention on behavioral intention and colonoscopy uptake in relatives of CRC patients, assessing the original additive model and an alternative model in which each theoretical construct contributes uniquely., Methods: We collected intention-to-screen and medical record-verified colonoscopy information on 218 individuals who received the personalized intervention., Results: Structural equation modeling showed poor main model fit (root mean square error of approximation (RMSEA) = 0.109; standardized root mean residual (SRMR) = 0.134; comparative fit index (CFI) = 0.797; Akaike information criterion (AIC) = 11,601; Bayesian information criterion (BIC) = 11,884). However, the alternative model (RMSEA = 0.070; SRMR = 0.105; CFI = 0.918; AIC = 11,186; BIC = 11,498) showed good fit. Cancer susceptibility (B = 0.319, p < 0.001) and colonoscopy self-efficacy (B = 0.364, p < 0.001) perceptions predicted intention to screen, which was significantly associated with colonoscopy uptake (B = 0.539, p < 0.001)., Conclusions: Our findings provide support of the utility of Extended Parallel Process Model for designing effective interventions to motivate CRC screening in persons at increased risk when individual elements of the model are considered. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Familial occurrence is common in colorectal cancer (CRC), but whether this increased familial risk differs by colonic subsite of the index patients CRC is not well understood., Aim: To quantify the risk of CRC in first-degree (FDR), second-degree (SDR) and first cousin (FC) relatives of individuals with CRC, stratified by subsite in the colorectum and age at diagnosis., Methods: Colorectal cancers diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age and gender-matched CRC-free controls were selected to form the comparison group for determining CRC risk in relatives using Cox regression analysis., Results: Of the 18,208 index patients diagnosed with CRC, 6584 (36.2%) were located in the proximal colon, 5986 (32.9%) in the distal colon and 5638 (31%) in the rectum. The elevated risk of CRC in relatives was similar in analysis stratified for CRC colorectal subsites in the index cases. FDR had similarly elevated risk of all site CRC, whether the index patient had cancer in the proximal colon [hazards ratio (HR): 1.85; 95% CI: 1.70-2.02], distal colon (HR: 1.90; 95% CI: 1.73-2.08) or rectum (HR: 1.83; 95% CI: 1.66-2.02) compared to relatives of controls. This risk was consistently greater for FDR when cases developed CRC below the age of 60 years., Conclusions: Relatives of CRC patients have a similarly elevated risk of CRC regardless of colonic tumour subsite in the index patient, and it is greatest for relatives of younger age index cases., (© 2015 John Wiley & Sons Ltd.)

Colorectal cancer (CRC) is the fourth most common cancer among men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis and several hamartomatous conditions. Up to 30% of CRC cases exhibit common familial risk, likely related to a combination of inherited factors and environment. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This article examines the colon cancer syndromes, their genetic basis, clinical management and evidence supporting colorectal screening. It also deals with the category of common (non-syndromic) familial risk including risk determination and screening guidelines.

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Background & Aims: Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah., Methods: All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database., Results: Of the 18,782 patients diagnosed with CRC, 134 were diagnosed with synchronous CRC (0.71%) and 300 were diagnosed with metachronous CRC (1.60%). The risk for synchronous CRC was significantly higher in men (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.02-2.06) and in patients aged 65 years or older (OR, 1.50; 95% CI, 1.02-2.21). Synchronous CRCs were located more often in the proximal colon (OR, 1.70; 95% CI, 1.20-2.41). First-degree relatives of cases with synchronous (OR, 1.86; 95% CI, 1.37-2.53), metachronous (OR, 2.34; 95% CI, 1.62-3.36), or solitary CRC (OR, 1.75; 95% CI, 1.63-1.88) were at increased risk for developing CRC, compared with relatives of CRC-free individuals. Four percent of first-degree relatives of patients with synchronous or metachronous cancer developed CRC at younger ages than the age recommended for initiating CRC screening (based on familial risk), and therefore would not have been screened., Conclusions: Of patients diagnosed with CRC, 2.3% are found to have synchronous lesions or develop metachronous CRC during follow-up evaluation. Relatives of these patients have a greater risk of CRC than those without a family history of CRC. These results highlight the importance of obtaining a thorough family history and adhering strictly to surveillance guidelines during management of high-risk patients., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)