Identification of candidate mediators of chemoresponse in breast cancer through therapy-driven selection of somatic variants

Abstract

Purpose More than a third of primary breast cancer patients are treated with cytotoxic chemotherapy, typically without guidance from predictive markers. Increased use of neoadjuvant chemotherapy provides opportunities for identification of molecules associated with treatment response, by comparing matched tumour samples before and after therapy. Our hypothesis was that somatic variants of increased prevalence after therapy promote resistance, while variants with reduced prevalence cause sensitivity. Methods We performed systematic analyses of matched pairs of cancer exomes from primary oestrogen receptor-positive/HER2-negative breast cancers (n = 6) treated with neoadjuvant epirubicin/cyclophosphamide. We identified candidate genes as mediators of chemotherapy response by consistent subclonal changes in somatic variant prevalence through therapy, predicted variant impact on gene function, and enrichment of specific functional pathways. Influence of candidate genes on breast cancer outcome was tested using publicly available breast cancer expression data (n = 1903). Results We identified 14 genes as the strongest candidate mediators of chemoresponse: TCHH, MUC17, ARAP2, FLG2, ABL1, CENPF, COL6A3, DMBT1, ITGA7, PLXNA1, S100PBP, SYNE1, ZFHX4, and CACNA1C. Genes contained somatic variants showing prevalence changes in up to 4 patients, with up to 3 being predicted as damaging. Genes coding for extra-cellular matrix components or related signalling pathways were significantly over-represented among variants showing prevalence changes. Expression of 5 genes (TCHH, ABL1, CENPF, S100PBP, and ZFHX4) was significantly associated with patient survival. Conclusions Genomic analysis of paired pre- and post-therapy samples resulting from neoadjuvant therapy provides a powerful method for identification of mediators of response. Genes we identified should be assessed as predictive markers or targets in chemo-sensitization.

Mechanisms of Resistance to Chemotherapy in Breast Cancer and Possible Targets in Drug Delivery Systems

“…Genetic markers have been explored as a predictor of the antitumor response or chemoresistance, and the use of next-generation sequencing provided a new perspective for marker identification. Several markers were previously associated with BC drug sensitivity or resistance [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. Gong et al [ 62 ] evaluated a cohort of 421 patients with luminal A BC from two different stages using genotyping from peripheral blood.…”

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

“…From a research perspective, neoadjuvant chemotherapy provides the further advantage that matched tumour tissue from pre- and post-therapy can be available, allowing for the comparative identification of the therapy-associated changes within the cancer cells that may be associated with relative chemotherapy resistance. This strategy has been used successfully by our team and others, to identify chemoresponse-associated somatic mutations [ 6 , 7 , 8 ], and changes in protein [ 9 , 10 ] or mRNA expression [ 8 , 11 ]. MicroRNAs have received less attention in this context, with only a total of five previous studies following this design [ 12 , 13 , 14 , 15 , 16 ], leading to identification of only one microRNA, miR-18a, as a potential mediator of chemoresistance [ 13 ].…”

CACNA1C is a prognostic predictor for patients with ovarian cancer

“…In line with previously published articles, CACNA1C was up-regulated in brain tumors, leukemia, breast cancer and other tumors [ 14 ]. Besides, variants of CACNA1C were associated with bladder cancer, endometrial cancer and breast cancer risk [ 15 , 32 , 33 ]. All of these indicated that CACNA1C could also be a prognostic predictor for patients with OC.…”