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Am J Hum Genet. 2019 Sep 5;105(3):526-533. doi: 10.1016/j.ajhg.2019.07.012. Epub 2019 Aug 15.

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

Author information

1
Department of Genetics, Northwestern University, Chicago, IL 60611, USA.
2
Department of Medicine (Medical Genetics), University of Washington School of Medicine, Seattle, WA 98195, USA.
3
Kaiser Permanente Washington, Seattle, WA 98101, USA.
4
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
5
Partners Laboratory of Molecular Medicine, Laboratory for Molecular Medicine, Partners Healthcare, Personalized Medicine, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Center for Genomic Center, Massachusetts General Hospital and The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
7
Department of Bioinformatics and Medical Education, University of Washington School of Medicine, Seattle, WA 98195, USA.
8
Department of Medicine (Medical Genetics), University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: pair@u.washington.edu.

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.

KEYWORDS:

actionable variant; cancer risk; clinical sequencing; colorectal cancer; genetic testing; incidental finding; panel sequencing; polyp

PMID:
31422818
PMCID:
PMC6731361
[Available on 2020-03-05]
DOI:
10.1016/j.ajhg.2019.07.012

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