TY - JOUR
T1 - A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients
AU - Wendt, Camilla
AU - Muranen, Taru A
AU - Mielikäinen, Lotta
AU - Thutkawkorapin, Jessada
AU - Blomqvist, Carl
AU - Jiao, Xiang
AU - Ehrencrona, Hans
AU - Tham, Emma
AU - Arver, Brita
AU - Melin, Beatrice
AU - Kuchinskaya, Ekaterina
AU - Stenmark Askmalm, Marie
AU - Paulsson-Karlsson, Ylva
AU - Einbeigi, Zakaria
AU - von Wachenfeldt Väppling, Anna
AU - Kalso, Eija
AU - Tasmuth, Tiina
AU - Kallioniemi, Anne
AU - Aittomäki, Kristiina
AU - Nevanlinna, Heli
AU - Borg, Åke
AU - Lindblom, Annika
N1 - © 2021. The Author(s).
PY - 2021/7/20
Y1 - 2021/7/20
N2 - 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.
AB - 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.
KW - Breast Neoplasms/genetics
KW - Case-Control Studies
KW - Checkpoint Kinase 2/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Germ-Line Mutation
KW - Humans
KW - Multifactorial Inheritance
KW - Sequence Deletion
KW - Exome Sequencing/methods
U2 - 10.1038/s41598-021-93926-x
DO - 10.1038/s41598-021-93926-x
M3 - Article
C2 - 34285278
SN - 2045-2322
VL - 11
SP - 1
EP - 9
JO - Scientific Reports
JF - Scientific Reports
M1 - 14763
ER -
