New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients
A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 establishe...
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Published in | Frontiers in genetics Vol. 11; p. 566266 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
24.09.2020
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Subjects | |
Online Access | Get full text |
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Summary: | A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as
APC
,
POLE
,
MSH2
or
PMS2
. The
MSH2
variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The
POLE
variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be
de novo
. One pathogenic
PMS2
variant was novel. We also identified a number of highly interesting variants of unknown significance in
APC
,
BUB1, TP53
and
RPS20
. The
RPS20
variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple
in silico
tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in
RPS20
expands the phenotypic spectrum of
RPS20
-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Cancer Genetics, a section of the journal Frontiers in Genetics Edited by: Steven M. Lipkin, Cornell University, United States Reviewed by: Elena Stoffel, University of Michigan, United States; Parvin Mehdipour, Tehran University of Medical Sciences, Iran These authors have contributed equally to this work Present address: Lukas A. Berchtold, AGC Biologics, Copenhagen, Denmark Anne-Bine Skytte, Cryos International, Aarhus, Denmark |
ISSN: | 1664-8021 1664-8021 |
DOI: | 10.3389/fgene.2020.566266 |