A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients
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 fam...
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Nature Portfolio
2021
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oai:doaj.org-article:602994982db2421bbe135a9df5feb72b2021-12-02T16:26:22ZA search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients10.1038/s41598-021-93926-x2045-2322https://doaj.org/article/602994982db2421bbe135a9df5feb72b2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93926-xhttps://doaj.org/toc/2045-2322Abstract 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.Camilla WendtTaru A. MuranenLotta MielikäinenJessada ThutkawkorapinCarl BlomqvistXiang JiaoHans EhrencronaEmma ThamBrita ArverBeatrice MelinEkaterina KuchinskayaMarie Stenmark AskmalmYlva Paulsson-KarlssonZakaria EinbeigiAnna von Wachenfeldt VäpplingEija KalsoTiina TasmuthAnne KallioniemiKristiina AittomäkiHeli NevanlinnaÅke BorgAnnika LindblomNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021) |
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Medicine R Science Q Camilla Wendt Taru A. Muranen Lotta Mielikäinen Jessada Thutkawkorapin Carl Blomqvist Xiang Jiao Hans Ehrencrona Emma Tham Brita Arver Beatrice Melin Ekaterina Kuchinskaya Marie Stenmark Askmalm Ylva Paulsson-Karlsson Zakaria Einbeigi Anna von Wachenfeldt Väppling Eija Kalso Tiina Tasmuth Anne Kallioniemi Kristiina Aittomäki Heli Nevanlinna Åke Borg Annika Lindblom A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients |
| description |
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. 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. |
| format |
article |
| author |
Camilla Wendt Taru A. Muranen Lotta Mielikäinen Jessada Thutkawkorapin Carl Blomqvist Xiang Jiao Hans Ehrencrona Emma Tham Brita Arver Beatrice Melin Ekaterina Kuchinskaya Marie Stenmark Askmalm Ylva Paulsson-Karlsson Zakaria Einbeigi Anna von Wachenfeldt Väppling Eija Kalso Tiina Tasmuth Anne Kallioniemi Kristiina Aittomäki Heli Nevanlinna Åke Borg Annika Lindblom |
| author_facet |
Camilla Wendt Taru A. Muranen Lotta Mielikäinen Jessada Thutkawkorapin Carl Blomqvist Xiang Jiao Hans Ehrencrona Emma Tham Brita Arver Beatrice Melin Ekaterina Kuchinskaya Marie Stenmark Askmalm Ylva Paulsson-Karlsson Zakaria Einbeigi Anna von Wachenfeldt Väppling Eija Kalso Tiina Tasmuth Anne Kallioniemi Kristiina Aittomäki Heli Nevanlinna Åke Borg Annika Lindblom |
| author_sort |
Camilla Wendt |
| title |
A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients |
| title_short |
A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients |
| title_full |
A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients |
| title_fullStr |
A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients |
| title_full_unstemmed |
A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients |
| title_sort |
search for modifying genetic factors in chek2:c.1100delc breast cancer patients |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/602994982db2421bbe135a9df5feb72b |
| work_keys_str_mv |
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