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Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.

ABSTRACT: As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable incidental findings genes. Those with CRC had a 3.8% rate of positive results (pathogenic or likely pathogenic) for a CRC-associated gene variant, despite generally being older at CRC onset (mean 72 years). Those ascertained for polyps had a 0.8% positive rate and those with no CRC/P had a positive rate of 0.2%. Though incidental finding rates unrelated to colon cancer were similar for all groups, our positive rate for cardiovascular findings exceeds disease prevalence, suggesting that variant interpretation challenges or low penetrance in these genes. The rate of HFE c.845G>A (p.Cys282Tyr) homozygotes in the CRC group reinforces a previously reported, but relatively unexplored, association between hemochromatosis and CRC. These results in a general clinical population suggest that current testing strategies could be improved in order to better detect Mendelian CRC-associated conditions. These data also underscore the need for additional functional and familial evidence to clarify the pathogenicity and penetrance of variants deemed pathogenic or likely pathogenic, particularly among the actionable genes associated with cardiovascular disease.

SUBMITTER: Gordon AS

PROVIDER: S-EPMC6731361 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.

Gordon Adam S AS Rosenthal Elisabeth A EA Carrell David S DS Amendola Laura M LM Dorschner Michael O MO Scrol Aaron A Stanaway Ian B IB DeVange Shannon S Ralston James D JD Zouk Hana H Rehm Heidi L HL Larson Eric E Crosslin David R DR Leppig Kathy A KA Jarvik Gail P GP

American journal of human genetics 20190815 3

As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. Th ...[more]

PMID: 31422818

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Project description:ImportanceThe Centers for Medicare & Medicaid Services added lung cancer screening with low-dose computed tomography (LDCT) as a Medicare preventive service benefit in 2015 following findings from the National Lung Screening Trial (NLST) that showed a 16% reduction in lung cancer mortality associated with LDCT. A challenge in developing and promoting a national lung cancer screening program is the high false-positive rate of LDCT because abnormal findings from thoracic imaging often trigger subsequent invasive diagnostic procedures and could lead to postprocedural complications.ObjectiveTo determine the complication rates and downstream medical costs associated with invasive diagnostic procedures performed for identification of lung abnormalities in the community setting.Design, setting, and participantsA retrospective cohort study of non-protocol-driven community practices captured in MarketScan Commercial Claims & Encounters and Medicare supplemental databases was conducted. A nationally representative sample of 344 510 patients aged 55 to 77 years who underwent invasive diagnostic procedures between 2008 and 2013 was included.Main outcomes and measuresOne-year complication rates were calculated for 4 groups of invasive diagnostic procedures. The complication rates and costs were further stratified by age group.ResultsOf the 344 510 individuals aged 55 to 77 years included in the study, 174 702 comprised the study group (109 363 [62.6%] women) and 169 808 served as the control group (106 007 [62.4%] women). The estimated complication rate was 22.2% (95% CI, 21.7%-22.7%) for individuals in the young age group and 23.8% (95% CI, 23.0%-24.6%) for those in the Medicare group; the rates were approximately twice as high as those reported in the NLST (9.8% and 8.5%, respectively). The mean incremental complication costs were $6320 (95% CI, $5863-$6777) for minor complications to $56 845 (95% CI, $47 953-$65 737) for major complications.Conclusions and relevanceThe rates of complications after invasive diagnostic procedures were higher than the rates reported in clinical trials. Physicians and patients should be aware of the potential risks of subsequent adverse events and their high downstream costs in the shared decision-making process.

Project description:BackgroundIndividuals with serrated polyps (SP) are at higher risk for synchronous colorectal advanced neoplasms (AN) and cancers. However, it remains unclear whether there is a unique involvement of the serrated pathway and/or the classical adenoma-carcinoma sequence in this setting.MethodsColorectal ANs, which include tubular adenomas ≥ 10 mm, adenomas with villous histology, high-grade intraepithelial neoplasms, and cancers, were collected retrospectively. The groups included ANs with (AN+SP) or without (AN-only) coexisting SPs. Clinicopathological findings were compared between groups. BRAF and KRAS mutations in ANs and SPs, and methylation levels at long interspersed element-1 (LINE-1) in adjacent mucosa were determined by pyrosequencing.ResultsSeventy-five ANs from 40 patients in the AN+SP group, and 179 ANs from 119 patients in the AN-only group were analyzed. There were no significant differences in clinicopathological findings between the two groups, except that intraepithelial neoplasia in the AN+SP group was more likely to be located in the right colon (P=0.018). BRAF mutations were significantly more frequent in the AN+SP group (P=0.003), while KRAS mutations showed no significant differences between groups (P=0.142). The majority of high-grade intraepithelial neoplasms in both groups showed a contiguous component of conventional adenoma. Individuals with large and right-sided SPs had significantly more conventional adenomas compared to those without such SPs (P=0.027 and P=0.031, respectively). Adjacent mucosa from individuals with multiple and large SPs showed significantly lower methylation levels at LINE-1 compared to individuals without such associated SPs (P=0.049 and P=0.015, respectively).ConclusionOur data suggest that both the adenoma-carcinoma sequence and the serrated pathway are operational in individuals with coexisting ANs and SPs. The reduced methylation levels at LINE-1 in the background mucosa suggest the possibility of an underlying 'field defect'.

Dataset Information

Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.

Publications

Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.

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