Cancer genetics articles from across Nature Portfolio

A genome-wide CRISPR/Cas9 screen in osimertinib-treated EGFR mutant cell lines identifies the Hippo pathway as an important non-genetic mechanism of cell survival in persister cells.

A single cell TCRseq method for dogs that robustly detects TCR expression suggests reannotation of some non-functional VJ genes between diverse between diverse repertoires of healthy dogs and expanded repertoires in malignancies.

Clinical classification of genomic variants identified on sequencing is often challenging, with many variants classified as Variants of Uncertain Significance (VUS) on account of insufficient evidence. Advances in sequencing and gene synthesis has made feasible multiplexed assays of variant effect (MAVEs), which quantify the functional impact of many thousands of genomic variants in a single experiment. These assays and the functional evidence they generate have the potential to empower more accurate clinical variant classification. However, there are many outstanding challenges and opportunities that require joint resolution and specification, thus necessitating communication between the research scientists who have designed and performed MAVEs and the clinicians and diagnostic scientists who will apply their data to clinical variant classification. In the ‘Clinical Application of MAVE Data’ workshop, held on 12th July 2023 at the Wellcome Connecting Science Conference Centre in between two relevant research meetings, ‘Curating the Clinical Genome 2023’ and the ‘Mutational Scanning Symposium 2023’, 44 key scientific and/or clinical stakeholders were brought together to consider important questions relating to clinical application of MAVE data, such as quantitative validation, variant truth-sets, platforms and standards for dissemination of MAVE data. The outcomes and possible next steps that were discussed encompassed development of focused workshops to develop consensus recommendations, creating a MAVE evaluation working group, and collaboration of ClinVar and MaveDB to enact software changes that support enhanced functional data submission.

Mitochondrial DNA mutations are present in over 50% of all cancers, and truncating mutations in several genes encoding components of complex I of the respiratory chain are most recurrent. We found that these mutations are a source of Warburg-like metabolic shifts that promote a pro-inflammatory immunological state, enhancing sensitivity to checkpoint blockade.

In a recent Developmental Cell paper, Falvo et al. establish a role for epigenetic memory of inflammatory injury in promoting pancreatic tumorigenesis.