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Whole genome sequencing reveals family cancer risk

Analysis of a study published in a science journal   |   By Dr Philippa Brice   |   Published 26 April 2011
Study: Identification of a Novel TP53 Cancer Susceptibility Mutation Through Whole-Genome Sequencing of a Patient With Therapy-Related AML
By: Link D.C. et al. (32 authors total)
In: The Journal of the American Medical Association
What this study set out to do:

Use whole-genome sequencing (WGS) to investigate possible cancer susceptibility mutations in a patient with early onset breast and ovarian tumours and therapy-related leukaemia, who had no family history of cancer or BRCA1/2 mutations. 

How they went about it:

The patient unfortunately died shortly after presentation with leukaemia, but researchers obtained consent to analyse samples of bone marrow and skin for a range of possible mutations (from single base changes to copy number variations and chromosomal abnormalities) using whole-genome sequencing, as well as the techniques SNP genotyping, gene expression profiling, and spectral karyotyping


A novel germline mutation was found in the known tumour suppressor gene TP53, and this was shown to prevent normal function of the TP53 protein. This deletion mutation was presumed to be de novo (a new mutation in the patient) as it was not present in the patient’s mother; the father’s DNA was not available for analysis, but there were no cancer cases among his near relatives. The leukaemia genome also showed a range of chromosomal abnormalities, many of them novel. 


The patient’s presentation and family history did not suggest Li-Fraumeni syndrome (a rare form of cancer susceptibility, often arising from TP53 mutations), so she had received TP53 testing; however, WGS revealed a germlineTP53 mutation. This has important clinical implications for the patient’s three children; if they have inherited the mutation, they will have a risk of around 50% of cancer before the age of 40, making screening to allow early detection and treatment very important. 

Our view:

Examples of the clinical utility of WGS for patients with serious and unexplained diseases are rapidly increasing. This case is interesting because it shows the value that a whole-genome approach could offer over current, targeted forms of genetic analysis to identify mutations (especially as costs fall), and additionally the potential medical benefits to the patient’s family. Fortunately, the researchers had included an option to communicate clinically relevant information to family members in their consent documents, because it will be important for a health professional to explain the potential risks to them. 

Photo credit: PLoS

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