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Bringing together germline and tumour genetic information for patient benefit


A fascinating session hosted by Professor Nazneen Rahman at the recent NCRI annual conference explored the potential value of integrating genetic information into the patient pathway

Posted on 12 November, 2015 by Brad Gellert

Over the past two decades, there has been a revolution in our understanding of the genes underlying the development and progression of cancer.

Increasingly researchers and clinicians are integrating that genetic information into the patient pathway, changing the way cancer is screened for, diagnosed and treated.

But there is more that can be done. A session at the recent National Cancer Research Institute conference in Liverpool argued that the development of optimal care was being inhibited by a tendency to analyse inherited genetic information, in the germline, and somatic mutations that arise in tumours, in their own separate silos.

Somatic mutations are those that are not inherited and can occur in any cell over a person’s lifetime – including in cancerous or precancerous cells.  Germline mutations, on the other hand, are those that are inherited and because they exist in the germ cell, are present in all other cells throughout the body. Traditionally however, these two fields of genetics have been separated at the research and clinical level – to the detriment of patients, it was argued.

Professor Nazneen Rahman, Head of Genetics and Epidemiology here at The Institute of Cancer Research, gave an interesting example at the session of the potential clinical value of converging somatic and germline mutation information. She talked about the interpretation and management of people with variants in the BRCA cancer predisposition genes. Combining germline and somatic information can lead to a better understanding of which BRCA variants are pathogenic – and harmful – and which are not.

It is understood that the overwhelming number of pathogenic BRCA mutations are protein-truncating variants. However, many other BRCA mutations – including the non-truncating variants – are commonly classified as variants of unknown significance, or VUS. 

Research has found that the tumour profile for people with a breast or ovarian BRCA VUS mutation is the same as those with a non-pathogenic mutation, and different from the pathogenic type.

The implications of this finding are enormous.

Professor Rahman argued that people with BRCA VUS mutations are often being inappropriately managed – in some cases harming patients. There is evidence that in the US 30 per cent of people receiving risk-reducing mastectomies had – in fact – a mutation that confers no clinical risk.

The theme was continued by Professor Dianna Eccles of the University of Southampton whose work found that young patients with HER2-mutant breast cancer rarely have a germline mutation in the BRCA gene. That suggests that although young people with HER2-mutant breast cancer may understandably ask questions about whether there is a genetic basis for their disease, a germline mutation test is unlikely to discover a causative mutation.

The research presented in the session raised a number of questions about how genetic information is currently being used – and can be used in future – to appropriately screen patients at high risk. Educating clinicians, as well as the public, will be essential if genetic information is going to be used to improve the outcomes of people with cancer, and those who could go on to develop it.


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