The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Abstract

Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, and ERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling. and sampling of tissue for this study. We also thank the Swedish National Breast Cancer Registry and Regional Cancer Center South for clinical data. The SweGen allele frequency data was generated

Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility

“…The datasets generated and analyzed during the current study which include: RNA-sequencing count data are publicly available as part of GSE182338 (Miyano et al, 2021; Sayaman et al, 2021; Shalabi et al, 2021). The data that support the findings of this study are available from GSE102088 (Song et al, 2017); GSE81540 (Brueffer et al, 2020; Brueffer et al, 2018; Dahlgren et al, 2021); The Cancer Genome Atlas (TCGA) Research Network: https://www.cancer.gov/tcga; and The Genotype-Tissue Expression (GTEx) Project: https://gtexportal.org/. Human mammary epithelial cells (HMECs) derived from subjects included in this study are available upon request.…”

“…For differential expression analysis in bulk normal primary breast tissue, GSE102088 (Song et al, 2017) microarray data (n=114) were downloaded from the Gene Expression Omnibus (GEO) database using the GEOquery (Davis & Meltzer, 2007). For machine learning, three data sets were used: (1) TCGA RNA-seq FPKM data from matched normal or PAM50 Normal, Luminal A (LumA), Luminal B (LumB), Her2 and Basal subtype breast cancer tissues (n=1,201) were downloaded using TCGAbiolinks (Colaprico et al, 2016) package; (2) GTEx RNA-seq count data from female subjects (n=180) were downloaded using the recount3 (Collado-Torres et al, 2017; Wilks et al, 2021) and FPKM transformed; and (3) GSE81540 (Brueffer et al, 2020; Brueffer et al, 2018; Dahlgren et al, 2021) RNA-seq FPKM data from PAM50 Normal, LumA, LumB, Her2 and Basal subtype breast cancer tissues (n=3,184) were downloaded from GEO.…”

Features of increased malignancy in eosinophilic clear cell renal cell carcinoma

“…Isolation and processing of RNA from tissue samples are described in supplementary material, Supplementary materials and methods. Analysis of the RNA sequencing data and additional data available from The Cancer Genome Atlas (TCGA) was performed as described previously [10] and in supplementary material, Supplementary materials and methods.…”

Changes of Mutations and Copy-number and Enhanced Cell Migration during Breast Tumorigenesis

“…These genes can be candidate genes for breast tumorigenesis and metastasis. Among the 81 genes that contain mutations exclusive to tumorigenic cells, ERBB2 [57] , FANCD2 [38,39] , MMP13 [40] , MSH2 [41] , RET [42] , ITCH [43] , CHD8 [44] , and SREBP-2 [45] have been previously reported to be associated with increased risk of breast cancer. It was demonstrated that the overall survival of patients of breast tumors containing ERBB2 mutations was lower than that of patients with wild type ERBB2 [57] .…”

“…Among the 81 genes that contain mutations exclusive to tumorigenic cells, ERBB2 [57] , FANCD2 [38,39] , MMP13 [40] , MSH2 [41] , RET [42] , ITCH [43] , CHD8 [44] , and SREBP-2 [45] have been previously reported to be associated with increased risk of breast cancer. It was demonstrated that the overall survival of patients of breast tumors containing ERBB2 mutations was lower than that of patients with wild type ERBB2 [57] . Other genes in the list include CLASP1, RAP2B, RET, and SEMA3E, all of which have a role in regulating cell migration or cell-matrix adhesion based on the Gene Ontology [58] .…”