No abstract

Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer.

Summary Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in the hormone-receptor driven prostate, breast, bladder, and salivary gland tumors3–8. However, how FOXA1 alterations affect cancer development is unclear, with FOXA1 previously ascribed both tumor suppressive9–11 and oncogenic12–14 roles. Here we assemble an aggregate cohort of 1546 prostate cancers (PCa) and show that FOXA1 alterations fall into three distinct structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class1 activating mutations originate in early PCa without ETS/SPOP alterations, selectively recur within the Wing2-region of the DNA-binding Forkhead domain (FKHD), enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen receptor (AR) program of prostate oncogenesis. By contrast, class2 activating mutations are acquired in metastatic PCa, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity, and through TLE3 inactivation promote WNT-pathway driven metastasis. Finally, class3 genomic rearrangements are enriched in metastatic PCa, comprise of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element, herein denoted FOXA1 Mastermind (FOXMIND), to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating AR-driven oncogenesis, and provides mechanistic insights into how different classes of FOXA1 alterations uniquely promote PCa initiation and/or metastatic progression. Furthermore, these results have direct implications in understanding the pathobiology of other hormone-receptor driven cancers and rationalize therapeutic co-targeting of FOXA1 activity.