RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer

Abstract

Breast cancer (BC) is the second leading cause of death in women. BC patients with family history or clinical features suggestive of inherited predisposition are candidate to genetic testing to determine whether a hereditary cancer syndrome is present. We aimed to identify new predisposing variants in familial BC patients using next-generation sequencing approaches. We performed whole exome sequencing (WES) in first-degree cousin pairs affected by hereditary BC negative at the BRCA1/2 (BReast CAncer gene 1/2) testing. Targeted analysis, for the genes resulting mutated via WES, was performed in additional 131 independent patients with a suspected hereditary predisposition (negative at the BRCA1/2 testing). We retrieved sequencing data for the mutated genes from WES of 197 Italian unrelated controls to perform a case-controls collapsing analysis. We found damaging variants in NPL (N-Acetylneuraminate Pyruvate Lyase), POLN (DNA Polymerase Nu), RASAL1 (RAS Protein Activator Like 1) and ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), shared by the corresponding cousin pairs. We demonstrated that the splice site alterations identified in NPL and ROS1 (in two different pairs, respectively) impaired the formation of the correct transcripts. Target analysis in additional patients identified novel and rare damaging variants in RASAL1 and ROS1, with a significant allele frequency increase in cases. Moreover, ROS1 achieved a significantly higher proportion of variants among cases in comparison to our internal control database of Italian subjects (p = 0.0401). Our findings indicate that germline variants in ROS1 and RASAL1 might confer susceptibility to BC.

Single‐cell combined with bulk‐RNA data reveal a pattern related to angiogenesis in breast cancer patients: Individualized medicine

“…Molecular biology studies have shown that, like other malignancies, the development of breast cancer is a complex process with multiple genes and factors interacting with each other. 12 Many advancements have been made in the treatment of breast cancer, but the pathways of its growth remain unclear.…”

“…In addition, breast cancer patients are prone to be depressed and anxious, resulting in somatic symptoms, such as fatigue, sleep disturbances, digestive disorders, feelings of helplessness and negativity, decreased immunity, increased blood pressure, and increased heart rate. Molecular biology studies have shown that, like other malignancies, the development of breast cancer is a complex process with multiple genes and factors interacting with each other 12 . Many advancements have been made in the treatment of breast cancer, but the pathways of its growth remain unclear.…”