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

• Published in: Scientific reports Vol. 11; no. 1; p. 14763
• Main Authors: Wendt, Camilla, Muranen, Taru A., Mielikäinen, Lotta, Thutkawkorapin, Jessada, Blomqvist, Carl, Jiao, Xiang, Ehrencrona, Hans, Tham, Emma, Arver, Brita, Melin, Beatrice, Kuchinskaya, Ekaterina, Stenmark Askmalm, Marie, Paulsson-Karlsson, Ylva, Einbeigi, Zakaria, von Wachenfeldt Väppling, Anna, Kalso, Eija, Tasmuth, Tiina, Kallioniemi, Anne, Aittomäki, Kristiina, Nevanlinna, Heli, Borg, Åke, Lindblom, Annika
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-07-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208; 631/67; 692/499; Alleles; Breast cancer; Breast Neoplasms/genetics; Cancer and Oncology; Cancer och onkologi; Case-Control Studies; Checkpoint Kinase 2/genetics; Clinical Medicine; Exome Sequencing/methods; Female; Gene frequency; Gene loci; Genetic factors; Genetic Predisposition to Disease; Genetics; Germ-Line Mutation; Health risks; Humanities and Social Sciences; Humans; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; multidisciplinary; Multifactorial Inheritance; Risk assessment; Science; Science (multidisciplinary); Sequence Deletion
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-93926-x

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.