Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients

Abstract

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.

Clinicopathologic and genomic characterizations of brain metastases using a comprehensive genomic panel

“…Such patients will benefit from reassessing their tumors for a better targeted therapy (see examples in Figure 4 ). We propose the routine use of CGP for brain metastasis patients similar to that described in our previous studies ( 18 , 19 , 41 ).…”

“…Previous literature has highlighted the need to explore the PI3K/AKT/mTOR pathway in aggressive tumors ( 19 ), and this includes brain metastatic tumors and their primary counterparts, suggesting the PI3K/AKT/mTOR pathway as a potential therapy target to prevent brain metastasis formation ( 20 , 21 ). PI3K/AKT/mTOR inhibitory agents that have been studied in literature, such as rapamycin and everolimus, which both inhibit mTOR, are expected to lead to better therapeutic responses compared to traditional treatment modalities in primary breast cancers ( 22 ).…”

Syringin Exerts Anti-Breast Cancer Effects Through PI3K-AKT and EGFR-RAS-RAF Pathways

“…The accuracy of these results needs to be based on data from more clinical samples. Studies have shown that PIK3CA and HRAS are prone to a mutation in a variety of tumors, resulting in their persistent hyperactivity, which promotes cancer cell proliferation and migration [39,40]. Therefore, this study analyzed 9536 BC samples from 18 studies via the cBioPortal database, and the results showed that the mutation rate of PIK3CA was 36%, while that of HRAS was only 1.1%.…”

Syringin exerts anti-breast cancer effects through PI3K-AKT and EGFR-RAS-RAF pathways

“…The accuracy of these results needs to be based on data from more clinical samples. Studies have shown that PIK3CA and HRAS are prone to a mutation in a variety of tumors, resulting in their persistent hyperactivity, which promotes cancer cell proliferation and migration [ 42 , 43 ]. Therefore, this study analyzed 9536 BC samples from 18 studies via the cBioPortal database, and the results showed that the mutation rate of PIK3CA was 36%, while that of HRAS was only 1.1%.…”