In the literature: October 2016

Correspondence to Professor Andres Cervantes; [email protected] MUTATIONAL SIGNATURES WITH POTENTIAL THERAPEUTIC INTEREST IN OESOPHAGEAL ADENOCARCINOMA A consortium on clinical and molecular stratification on oesophageal adenocarcinoma established in Britain has recently published in Nature Genetics, a whole-genomic sequencing analysis of more than 100 samples. Interestingly, they describe three distinct molecular subtypes with potential treatment relevance. This observation has also been verified in an independent validation cohort. Those three types are: (1) the ones showing homologous recombination and chromosome segregation pathways defects with enrichment of a BRCA signature. These tumours would be sensitive to DNA damaging agents, including neutron and photon irradiation with the addition of PARP inhibitors, (2) a group with high mutational load and neoantigen burden, associated with an increased CD8+ T-cell density and with a dominant T>G mutational pattern, in which immunotherapy with anti-PD1 or PDL1 antibodies could have a role and (3) evidence of an ageing imprint with a C>A/T pattern and fewer unstable genomes and large duplication events, which may be sensitive to chemotherapy and antiHER2 or MET directed therapies. The clinical characteristics of the three subgroups did not differ significantly, implying that the classification, and hence spectrum of mutation patterns, does not vary with smoking, age, sex, tumour histopathological grade, tumour stage, response to chemotherapy, overall or recurrence-free survival, etc. Therefore, the mutation signature profiles seem to be capturing a different type of information compared with current clinical classification methods. Although the authors propose that these subtypes could be ascertained using a clinically applicable sequencing strategy as a basis for treatment selection, further studies will be required for preclinical validation before implementation in trials, as well as to understand the extent to which this genomic distinction is maintained downstream, at the level of the transcriptome, proteome and cellular phenotype. INFREQUENT SOMATIC MUTATIONS IN LUNG CANCER MAY BE DRIVERS AND CAN INDUCE MEK-DEPENDENT RESISTANCE TO ANTI-EGFR DRUGS Investigators at Dana Farber and Broad Institute in Harvard have reported an expression-based variant-impact phenotyping (eVIP) method to distinguish impactful from neutral somatic mutations. The method identified rare gain-of-function mutations in oncogenes and widespread inactivation of tumour suppressors by missense variation. eVIP was able to identify 69% of mutations analysed as impactful and 31% as functionally neutral. The application of this approach also showed that 92% of missense variants in tumour suppressor genes KEAP1 and STK11 were identified as loss-of-function variants. A subset of the impactful mutations induces xenograft tumour formation in mice and/or confers resistance to cellular epidermal growth factor receptor (EGFR) inhibition. Combining eVIP with assays for cancer phenotypes identified over a dozen rare, noncanonical mutations as gain-of-function, likely ‘driver’, oncogenic mutations. Variants of ARAF, BRAF, EGFR, ERBB2, KRAS and RIT1 are shown to be oncogenic and to induce MEK-dependent resistance to EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T and multiple BRAF variants, demonstrating that rare mutations can be functionally important in lung adenocarcinomas. The findings also support the proof of principle that high-throughput phenotyping of somatic mutations can distinguish impactful mutations from neutral mutations and generate valuable insights into patterns of functional mutations in cancer. These efforts are amenable to extension to include testing of germ-line and somatic variants and the use of genome-editing techniques to study endogenous mutations. Such future efforts might include saturating mutagenesis analysis of a small number of clinically actionable genes as well as a broad survey of mutated alleles in diverse genes. Moreover,