Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

Abstract

Germline pathogenic variants in BRCA1 and BRCA2 increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for BRCA1 and BRCA2 pathogenic variants has become an important part of clinical practice for cancer risk assessment and for reducing individual risk of developing cancer. Genetic testing can produce three outcomes: positive (a pathogenic variant), uninformative (no pathogenic variant) and uncertain significance (a variant of unknown clinical significance). More than one third of BRCA1 and BRCA2 variants identified have been classified as variants of uncertain significance, presenting a challenge for clinicians. To address this important clinical challenge, a number of studies have been undertaken to establish a gene expression phenotype for pathogenic BRCA1 and BRCA2 variant carriers in several diseased and normal tissues. However, the consistency of gene expression phenotypes described in studies has been poor. To determine if gene expression analysis has been a successful approach for variant classification, we describe the design and comparability of 23 published gene expression studies that have profiled cells from BRCA1 and BRCA2 pathogenic variant carriers. We show the impact of advancements in expression-based technologies, the importance of developing larger study cohorts and the necessity to better understand variables affecting gene expression profiles across different tissue types.

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“…Through phylogenetic analysis, by comparing data in all three candidate species most closely related genes are observed. Hence, it is concluded that BRCA2 genes maintained their function even after divergence in humans, chimpanzee and western gorilla [21,22].…”

Increased gene expression variability in BRCA1-associated and basal-like breast tumours

“…Despite representing distinct tumour types, there has been limited success in identifying gene expression profiles related to BRCA1 and BRCA2 pathogenic variants in either tumour [3,[21][22][23][24] or normal tissue [25][26][27][28]. Across all studies, consensus on altered genes and pathways has been poor, with gene expression profiles influenced by study design rather than variant classification [29]. For example, early studies were confounded by differences in oestrogen receptor (ER) status of BRCA1-associated tumours compared to sporadic [21].…”