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A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

Wendt, Camilla ; Muranen, Taru A ; Mielikäinen, Lotta ; Thutkawkorapin, Jessada ; Blomqvist, Carl ; Jiao, Xiang ; Ehrencrona, Hans LU orcid ; Tham, Emma ; Arver, Brita and Melin, Beatrice , et al. (2021) In Scientific Reports 11. p.1-9
Abstract

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls.... (More)

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast Neoplasms/genetics, Case-Control Studies, Checkpoint Kinase 2/genetics, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Multifactorial Inheritance, Sequence Deletion, Exome Sequencing/methods
in
Scientific Reports
volume
11
article number
14763
pages
1 - 9
publisher
Nature Publishing Group
external identifiers
  • scopus:85111079800
  • pmid:34285278
ISSN
2045-2322
DOI
10.1038/s41598-021-93926-x
language
English
LU publication?
yes
additional info
© 2021. The Author(s).
id
756e85d2-89c6-4498-bc7b-9f89a7da8958
date added to LUP
2023-09-01 17:10:19
date last changed
2024-04-06 00:02:44
@article{756e85d2-89c6-4498-bc7b-9f89a7da8958,
  abstract     = {{<p>The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.</p>}},
  author       = {{Wendt, Camilla and Muranen, Taru A and Mielikäinen, Lotta and Thutkawkorapin, Jessada and Blomqvist, Carl and Jiao, Xiang and Ehrencrona, Hans and Tham, Emma and Arver, Brita and Melin, Beatrice and Kuchinskaya, Ekaterina and Stenmark Askmalm, Marie and Paulsson-Karlsson, Ylva and Einbeigi, Zakaria and von Wachenfeldt Väppling, Anna and Kalso, Eija and Tasmuth, Tiina and Kallioniemi, Anne and Aittomäki, Kristiina and Nevanlinna, Heli and Borg, Åke and Lindblom, Annika}},
  issn         = {{2045-2322}},
  keywords     = {{Breast Neoplasms/genetics; Case-Control Studies; Checkpoint Kinase 2/genetics; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Multifactorial Inheritance; Sequence Deletion; Exome Sequencing/methods}},
  language     = {{eng}},
  month        = {{07}},
  pages        = {{1--9}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-93926-x}},
  doi          = {{10.1038/s41598-021-93926-x}},
  volume       = {{11}},
  year         = {{2021}},
}