Genomic-transcriptomic evolution in lung cancer and metastasis.

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

Letter - Response to 'How to protect general practice from child protection'

The bad news is that the BJGP published under such a negative and provocative title without balanced debate, in contrast to the recent BMJ head-to-head debate 'Has child protection become a form of madness'.1,2 One interesting comparison made in that debate is that Sweden and Finland spend 50% more of their gross domestic product on children and families than we do in the UK, we spend 200% more than they do on social problems. In my view these figures help us understand societal attitudes that have knock-on effects through all services for children and families including general practice. The current UK GP contract is certainly not child and family friendly and it is unlikely that current NHS changes will improve matters.Mike Fitzpatrick's latest letter over-emphasises the personal while flagging up the real difficulties for general practice.3 My work as a frontline GP and my statutory role as a named doctor for safeguarding children allows me to understand these difficulties, and indeed the importance of making vulnerable adults safe that he highlights in the same Journal.4The good news is that the great majority of children grow up well and happy in their families and GP practices support them in this. I emphasise this when delivering safeguarding training to GPs. In doing this work GPs can develop a sense of why something is going wrong. With appropriate use of their knowledge, skills, and information, GPs can address the needs of children and their families across the spectrum of vulnerability and need through to abuse and neglect. There is no question that this is challenging, but in the UK all professionals are obliged by statute to fulfil our professional roles and responsibilities. Those specific to general practice are on pages 60-63 of Working Together to Safeguard Children 2012.5GP colleagues in Cornwall show appreciation of the importance of safeguarding, but many feel there is too much guidance and insufficient resources. The majority of the practices value the RCGP/NSPCC Toolkit for Safeguarding Adults and Young People, that being written for GPs by GPs helps practices establish policies and procedures on safeguarding which work.6 I commend the RCGP for grasping the safeguarding nettle, collaborating with the NSPCC to produce this toolkit, and including safeguarding as one of the ten priorities of the RCGP Child Health Strategy for 2012-15.7 Can the BJGP help the College bring this strategy forward? Up to 25% of our patients are children. They are the future of the UK.