Recurrent and functional regulatory mutations in breast cancer

Abstract

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…RMRP acts as a sponge for miR-206 an oncogene in lung cancer (Meng, et al 2016). Deep sequencing of 360 primary breast tumors identified mutations in the promoters of lncRNAs RMRP and NEAT1 that increased their expression and noted increased expression of these lncRNAs in breast tumors (Rheinbay, et al 2017). However, RMRP's role in BCa remains to be fully elucidates and no publications were found with respect to RMRP in prostate, endometrial, ovarian, or thyroid cancer.…”

Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

“…Epigenetic adaptations may provide initial resistance and allow tumor cells to survive until they acquire secondary mutations that further drive progression (16,45,46). Furthermore, mutations in noncoding regions, such as enhancers and promoters, influence gene expression and can be new drivers for cancer progression and evolution (47)(48)(49).…”

Hundreds of Putative Non-Coding Cis-Regulatory Drivers in Chronic Lymphocytic Leukaemia and Skin Cancer

“…There are examples where the non-coding regulatory mutations are involved in tumorigenesis like the TERT promoter in melanoma (Horn et al, 2013;Huang et al, 2013) and in other cancers (Vinagre et al, 2013), and recurrent non-coding mutations in chronic lymphocytic leukaemia (CLL) (Puente et al, 2015) and breast cancer (Rheinbay et al, 2017). However, these studies have each identified a small number of .…”