Uncovering rare somatic variants in olfactory receptor genes in Pakistani triple-negative breast cancer patients

Breast cancer is a heterogeneous illness in terms of histologic variants, natural history of disease, clinical behaviour, and response to therapy. Triple-negative breast cancer (TNBC) is a biologically aggressive tumour with the worst prognosis among all subtypes, owing to higher grade and high proliferation capacity, and, restricted therapeutic choices. Despite numerous attempts to identify therapeutic aberrations that can be targeted, chemotherapy continues to be the primary systemic treatment for TNBC. It should be noted, however, that multiple studies have shown racial variation in the clinical behaviour of TNBCs and there remains a need to identify alternative, novel driver mutations in our ethnically diverse population, especially actionable mutations that might prove to be potential targets for precision therapy. This study was taken up with the aim to identify distinct targetable genetic alterations in TNBC patients and to report the frequencies of various subtypes.

Among 353 breast cancer patients, 75 were TNBC, and 10 treatment-naïve TNBC cases were selected for the study. Selected TNBC FFPE (formalin fixed paraffin embedded) tissue samples were subjected to Genomic DNA extraction and whole-exome sequencing followed by bioinformatics analysis for detection of deleterious variants. A total of 812,598 non-synonymous SNPs were identified over the 10 samples. Following application of insilico prediction tools, 275 SNPs were identified. The most frequently mutated genes were OR9G1 and MUC6. Six out of 10 TNBC cases in this study were found to harbour missense variants, c.505 C > T (p.Arg169Cys) and c.335 A > G (p.Tyr112Cys) in the OR9G1 gene. The second most frequently mutated gene in our samples was MUC6 with 5 samples harbouring the variant c.5618 C > A.

Detection of these variants in six out of 10 cases indicates probable role of these vastly unexplored genes in the pathogenesis of triple-negative breast tumours and warrants further exploration to establish their significance as targetable sites and facilitate drug development.