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Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer

Djursby, Malene ; Hansen, Thomas van Overeem ; Wadt, Karin A.W. ; Madsen, Majbritt Busk ; Berchtold, Lukas Adrian ; Lautrup, Charlotte Kvist ; Markholt, Sara ; Jensen, Uffe Birk ; Krogh, Lotte Nylandsted and Lundsgaard, Malene , et al. (2022) In Human Genetics 141(12). p.1925-1933
Abstract

The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch... (More)

The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Genetics
volume
141
issue
12
pages
1925 - 1933
publisher
Springer
external identifiers
  • scopus:85135256127
  • pmid:35904628
ISSN
0340-6717
DOI
10.1007/s00439-022-02470-9
language
English
LU publication?
yes
id
9efd61fc-50d3-4b51-b33b-1d2c14df5268
date added to LUP
2022-11-02 14:33:33
date last changed
2024-05-30 14:53:55
@article{9efd61fc-50d3-4b51-b33b-1d2c14df5268,
  abstract     = {{<p>The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset &gt; age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.</p>}},
  author       = {{Djursby, Malene and Hansen, Thomas van Overeem and Wadt, Karin A.W. and Madsen, Majbritt Busk and Berchtold, Lukas Adrian and Lautrup, Charlotte Kvist and Markholt, Sara and Jensen, Uffe Birk and Krogh, Lotte Nylandsted and Lundsgaard, Malene and Gerdes, Anne Marie and Nilbert, Mef and Therkildsen, Christina}},
  issn         = {{0340-6717}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{1925--1933}},
  publisher    = {{Springer}},
  series       = {{Human Genetics}},
  title        = {{Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer}},
  url          = {{http://dx.doi.org/10.1007/s00439-022-02470-9}},
  doi          = {{10.1007/s00439-022-02470-9}},
  volume       = {{141}},
  year         = {{2022}},
}