Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients
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Duna H. Barakeh1, Rasha Aljelaify2, Yara Bashawri3, Amal Almutairi2, Fatimah Alqubaishi2, Mohammed Alnamnakani4, Latifa Almubarak2, Abdulrahman Al Naeem5, Fatema Almushawah6, May Alrashed7,8 and Malak Abedalthagafi2
1 Department of Pathology, King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia
2 Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia
3 Department of Biostatistics, Research Centre, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
4 Department of Pathology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
5 Department of Radiology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
6 Department of Surgery, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
7 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
8 Chair of Medical and Molecular Genetics Research, King Saud University, Riyadh, Kingdom of Saudi Arabia
Keywords: breast cancer; PIK3CA; BCa; Saudi Arabia; BRCA
Received: November 17, 2020 Accepted: February 19, 2021 Published: March 30, 2021
Breast cancer (BCa) ranks first in incidence rate among cancers in Arab females. The association between genetic polymorphisms in tumor suppressor genes and the risk of BCa has been studied in many ethnic populations with conflicting conclusions while Arab females and Saudi Arabian studies are still lacking. We screened a cohort of Saudi BCa patients by NGS using a bespoke gene panel to clarify the genetic landscape of this population, correlating and assessing genetic findings with clinical outcomes. We identified a total of 263 mutations spanning 51 genes, including several frequently mutated. Among the genes analyzed, the highest mutation rates were found in PIK3CA (12.9%), BRCA2 (11.7%), BRCA1 (10.2%), TP53 (6.0%), MSH2 (3.8%), PMS2 (3.8%), BARD1 (3.8%), MLH1 (3.4%), CDH1 (3.0%), RAD50 (3.0%), MSH6 (3.0%), NF1 (2.6%), in addition to others. We identified multiple common recurrent variants and previously reported mutations. We also identified 46 novel variants in 22 genes that were predicted to have a pathogenic effect. Survival analysis according to the four most common mutations (BRCA1, BRCA2, TP53, and PIK3CA) showed reduced survival in BRCA1 and BRCA2-mutant patients compared to total patients. Moreover, BRCA2 was demonstrated as an independent predictor of reduced survival using independent Cox proportional hazard models.
We reveal the landscape of the mutations associated with BCa in Saudi women, highlighting the importance of routine genetic sequencing in implementation of precision therapies in KSA.
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