Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity
Breast cancer (BC) is the most prevalent malignancy among women worldwide with germline pathogenic variants/likely pathogenic variants (PVs/LPVs) in BRCA1/2 accounting for a large portion of hereditary cases. Recently, heterozygous PVs/LPVs in the ATM serine/threonine kinase or Ataxia-telangiectasia...
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Published in | Scientific reports Vol. 13; no. 1; p. 20924 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
27.11.2023
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | Breast cancer (BC) is the most prevalent malignancy among women worldwide with germline pathogenic variants/likely pathogenic variants (PVs/LPVs) in
BRCA1/2
accounting for a large portion of hereditary cases. Recently, heterozygous PVs/LPVs in the ATM serine/threonine kinase or Ataxia-telangiectasia mutated gene (
ATM
) has been identified as a moderate susceptibility factor for BC in diverse ethnicities. However, the prevalence of
ATM
PVs/LPVs in BC susceptibility in Arab populations remains largely unexplored. This study investigated the prevalence of
ATM
PVs/LPVs among BC patients from Saudi Arabia, employing capture-sequencing technology for
ATM
PVs/LPVs screening in a cohort of 715 unselected BC patients without
BRCA1/2
PVs/LPVs. In addition, founder mutation analysis was conducted using the PHASE program. In our entire cohort, four unique PVs/LPVs in the
ATM
gene were identified in six cases (0.8%). Notably, one recurrent LPV, c.6115G > A:p.Glu2039Lys was identified in three cases, for which haplotype analysis confirmed as a novel putative founder mutation traced back to 13 generations on average. This founder mutation accounted for half of all identified mutant cases and 0.4% of total screened cases. This study further reveals a significant correlation between the presence of
ATM
mutation and family history of BC (p = 0.0127). These findings underscore an approximate 0.8% prevalence of
ATM
germline PVs/LPVs in Arab BC patients without
BRCA1/2
PVs/LPVs and suggest a founder effect of specific recurrent
ATM
mutation. These insights can help in the design of a genetic testing strategy tailored to the local population in Saudi Arabia, thereby, enabling more accurate clinical management and risk prediction. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-023-48231-0 |