Editors' ChoiceCancer

CuRBing cancer’s enthusiasm

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Science Translational Medicine  15 May 2019:
Vol. 11, Issue 492, eaax1715
DOI: 10.1126/scitranslmed.aax1715

Abstract

A gene expression signature of biallelic RB1 loss identifies more aggressive tumors.

The RB1 gene encoding the tumor suppressor protein pRB—named for the discovery of its mutations in familial retinoblastoma—is one of the top mutated genes in more than 20 cancer types. The best-known role for pRB is its direct binding and inhibition of E2F transcription factors, which under normal circumstances prevents cells from entering S phase, effectively suppressing growth. Several molecular analyses, including those from The Cancer Genome Atlas (TCGA), showed that RB1 mutations also include large deletions encompassing some or all of the gene. Moreover, correlative studies of patients receiving therapy for early and advanced cancers have shown relationships between RB1 loss and sensitivity to treatment (such as CDK4/6 inhibitors in breast cancer) or resistance to treatment (such as antiandrogen therapy in prostate cancer).

In this study, Chen and colleagues address the challenge of identifying tumors that have hits to both copies of RB1 by generating a unified gene expression signature reflecting multiple cancer types. First, the authors used mutation and copy number data from the Cancer Cell Line Encyclopedia to identify which of the 951 cell lines harbored two hits to RB1, either as mutations or deletions. Then, using matched gene expression microarray data, the authors generated a candidate list of genes that were differentially expressed between RB-intact and RB-deficient cells. They refined this signature against a dataset of 11,007 tumors with matched copy number and mutation data to generate a 144-gene RB1-loss signature (RBS).

Last, the authors examined progression-free survival in the pan-cancer TCGA dataset and overall survival in an independent dataset of 101 metastatic prostate cancers. In both cohorts, RBS identified subjects with shorter survival times. Interestingly, not all cases had obvious genomic disruptions to RB1, indicating that the signature may also identify tumors with an impaired pRB pathway. Because loss of RB1 is associated with tumor aggressiveness and treatment response, these results suggest that applying the RBS to tumor biopsies would allow for further personalization of treatment. Future randomized trials are needed to determine whether treatment decisions based on RBS improve patient outcomes.

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