Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer

Abstract

The colony stimulating factor 2 receptor subunit beta (CSF2RB) is the common signaling subunit of the cytokine receptors for IL‐3, IL‐5, and GM‐CSF. Several studies have shown that spontaneous and random mutants of CSF2RB can lead to ligand independence in vitro. To date, no report(s) have been shown for the presence of potentially transforming and oncogenic CSF2RB mutation(s) clinically in cancer patients until the first reported case of a leukemia patient in 2016 harboring a germline‐activating mutation (R461C). We combined exome sequencing, pathway analyses, and functional assays to identify novel somatic mutations in KAIMRC1 cells and breast tumor specimen. The patient’s peripheral blood mononuclear cell (PBMC) exome served as a germline control in the identification of somatic mutations. Here, we report the discovery of a novel potentially transforming and oncogenic somatic mutation (S230I) in the CSF2RB gene of a breast cancer patient and the cell line, KAIMRC1 established from her breast tumor tissue. KAIMRC1 cells are immortalized and shown to survive and proliferate in ligand starvation condition. Immunoblot analysis showed that mutant CSF2RB signals through JAK2/STAT and PI3K/mTOR pathways in ligand starvation conditions. Screening a small molecule kinase inhibitor library revealed potent JAK2 inhibitors against KAIMRC1 cells. We, for the first time, identified a somatic, potentially transforming, and oncogenic CSF2RB mutation (S230I) in breast cancer patients that seem to be an actionable mutation leading to the development of new therapeutics for breast cancer.

Uncovering Hidden Cancer Self-Dependencies through Analysis of shRNA-Level Dependency Scores

“…In addition, unreported genes in IntOGen such as CANT1, IL20RA, BRX1, BUB1, ATIC, Twist2 , and CSF2RB were identified by the NBDep method as putative missense mutational cancer genes but these genes were not detected by using APSiC on ATARiS and DEMETER2 gene-level scores. Recently, the important role of these genes as driver genes in different stages of cancer has been presented [29-35]. As depicted in Supplementary Figure S2, there was a significant PPI enrichment observed for both the identified missense driver genes and the identified genes not reported in IntOGen, with p-values of 0.000214 and 0.00767, respectively.…”

“…Recently, the important role of these genes as driver genes in different stages of cancer has been presented [29][30][31][32][33][34][35]. As depicted in Supplementary Figure S2, there was a significant PPI enrichment observed for both the identified missense driver genes and the identified genes not reported in IntOGen, with p-values of 0.000214 and 0.00767, respectively.…”

Uncovering hidden cancer self-dependencies through analysis of shRNA-level dependency scores

“…In addition, unreported genes in IntOGen such as CANT1 , IL20RA , BRX1 , BUB1 , ATIC , Twist2 , and CSF2RB were identified by the NBDep method as putative missense mutational cancer genes but these genes were not detected by using APSiC on ATARiS and DEMETER2 gene-level scores. Recently, the important role of these genes as driver genes in different stages of cancer has been presented 36 – 42 . Box plots depicting the standardized, denoised ranks of four example genes identified by the NBDep algorithm are displayed in Fig.…”

Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease

“…Although studies so far have not suggested geographic or population differences in PAP occurrence, the most common PAP co-morbidities include cardiovascular disease, type 2 diabetes, and hypertension, all of which are unevenly distributed among populations. Further, a rare Arg461Cys CSF2RB variant (MAF< 0.001, not listed in Table 6 ) was found in individual patients with leukemia ( 355 ) and breast cancer ( 356 ). Notably, both of these cancers show racial and ethnic disparities [ 430 and 352 respectively].…”