Genomic and Expression Analyses Define MUC17 and PCNX1 as Predictors of Chemotherapy Response in Breast Cancer

Abstract

This is a repository copy of Genomic and expression analyses define MUC17 and PCNX1 as predictors of chemotherapy response in breast cancer.

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

“…This has already been described in detail [6], a brief summary follows. Ethical approval for this work was obtained from Leeds (East) REC (ref.…”

“…Whole-exome sequencing data were processed as previously described [6] using open-source bioinformatics tools by Edinburgh Genomics Laboratory (Edinburgh, UK). In summary, adapters, primers and poor-quality bases were trimmed using cutadapt (v1.8.3) [13] and trimmed reads were aligned to reference genome Hg19 using BWA-MEM (v0.7.15) [14].…”

“…A consequence of the increased use of neoadjuvant protocols is the availability for research purposes of matched samples of primary tumour tissue taken before systemic therapy, usually in the form of a diagnostic biopsy, and after therapy from the resection. These matched samples present a powerful resource for study of the molecular response of tumours to therapy, and thereby to identify pathways associated with relative therapy resistance or sensitivity [5][6][7]. The hypothesis behind such analyses is that tumour cells that remain after therapy include characteristics associated with therapy resistance, while characteristics present before therapy but lost in the matched post-treatment sample include molecular events associated with relative therapy sensitivity.…”

“…With respect to cancer genomics, this hypothesis implies that somatic variants that expand in prevalence after therapy may promote resistance, while somatic variants that are eliminated or reduced in prevalence may be associated with therapy sensitivity [6]. However, such studies are in their infancy for solid cancers as they are limited by technical and analytical challenges relating to the small size of samples, whether these samples are representative of the diversity of somatic clones throughout the tumour, whether variable infiltration with non-cancer (stromal) cells invalidates assessment of variant prevalence, and the difficulty of separating functionally response-modifying variants from passengers.…”

“…We have recently performed a study into the genomic selection cytotoxic chemotherapy exerts on primary breast cancers using this matched pre-and post-therapy design [6]. Importantly, we used laser microdissection to select tumour cells from samples before sequencing whole cancer exomes, in order to allow comparison of the prevalence of somatic variants without the confounder of variable stromal contamination.…”