Affiliation:
1. Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center
2. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre
3. Department of Surgery, King Faisal Specialist Hospital and Research Centre
Abstract
Abstract
Background
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 remain largely unexplored.
Methods
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 PHASE program.
Results
In our entire cohort, four unique PVs/LPVs in 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).
Conclusions
These finding underscore an approximate 0.8% prevalence of ATM germline PVs/LPVs in Arab BC patients without BRCA1/2 PVs/LPVs and suggested 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.
Publisher
Research Square Platform LLC