Abstract A42: Identifying relationships between high expression levels of the HSPA9 gene, putative HSPA9 alterations, and patient survivability in invasive breast carcinomas

Abstract

Metastasis is the primary cause for the lethality of breast cancer, and is responsible for approximately 90% of breast cancer-related deaths. Tumor cell resistance to cancer treatment continues to stymie efforts to effectively treat breast cancer, which we know to be primarily mediated by a highly conserved molecular chaperone in the heat shock protein 70 family known as mortalin. Mortalin is encoded by the gene HSPA9B localized on chromosome 5q31.1.1, and is low or undetectable in normal unstressed cells while highly expressed in many carcinomas. Breast cancer cell invasion and metastasis are closely related to adverse clinical outcomes and a worsened prognosis for patients. Previous studies have shown that breast cancer patients with high mortalin expression had decreased DFS and OS rates compared to those with low mortalin expression in early- or late-stage breast cancer. Conversely, low expression of mortalin decreases tumor cell progression and inhibits the epithelial-mesenchymal transition. Gene amplification is one of the major pathways by which proto-oncogenes are activated during tumorigenesis, and missense mutations in the gene of interest could potentially render a nonfunctional mortalin product. We examined three different publicly available datasets from the Genome Data Commons for possible relationships between alterations in the HSPA9 gene and BRCA patient survival rates. On a mutation-specific level, we compared the survival rates of the cases with a high frequency of HSPA9 alterations versus the cases without HSPA9 alterations. Our bioinformatics analysis of the BRCA datasets showed fourteen alterations in the HSPA9 gene that correlated to prognosis and survival rate in patients with breast cancer. Amplifications in the HSPA9 gene lead to lower survivability rates for the patient samples, while missense mutations in HSPA9 led to higher survivability rates. Also of interest, missense mutations were far more numerous than any other HSPA9 alteration type. Different alterations in the HSPA9 gene result in different mortalin protein products, ultimately leading to differences in prognosis for patients with invasive breast carcinomas. Our study supports that much of the clinically observable plasticity and heterogeneity occurs within, rather than across, the major biologic subtypes of breast cancer suggested by the variance in HSPA9 alteration types. Furthermore, the study supports that mortalin expression has a significant effect on breast cancer status and lends credence to mortalin as a survival predictor, particularly in BRCA patients. Note: This abstract was not presented at the conference. Citation Format: Kofi K. Khamit-Kush, James W. Lillard, Jr., Vincent C. Bond, Ming Huang, William Roth. Identifying relationships between high expression levels of the HSPA9 gene, putative HSPA9 alterations, and patient survivability in invasive breast carcinomas [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A42.