Better genetic risk prediction for colorectal and womb cancer

6 January 2014

A new classification scheme for variants in genes associated with inherited forms of colorectal and womb cancer should help improve clinical management of affected families.
 
Lynch syndrome (or hereditary nonpolyposis colorectal cancer, HNPCC) is an inherited disorder that results in increased risk of a range of cancers, especially colon and bowel (colorectal) and endometrial cancer. The condition typically arises from heritable mutations in a small number of specific genes: MLH1MSH2MSH6 and PMS2.
 
Now the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) has developed a new clinical classification scheme for genetic variants within these key genes, published in in the journal Nature Genetics. This is important because the clinical implications of any given variant affect how patients and family members in whom the variant is identified are managed, in terms of risk prediction, surveillance and treatment.
 
Presently, although genetic testing is available for patients in whom Lynch syndrome is suspected, many receive results of unknown clinical significance.
 
The international team of researchers and clinicians examined both published and unpublished clinical and functional data (from multiple genetic data repositories) on more than 2,300 specific mutations within the genes. Preliminary classification was further refined by multidisciplinary expert committee, with variants assigned to five classes: pathogenic, likely pathogenic, uncertain, likely not pathogenic and not pathogenic.
 
A third of database entries reviewed received revised clinical classifications, and the new InSiGHT Colon Cancer Gene Variant Database for MMR and other colon cancer contains more than 1,300 entries that previously lacked known clinical associations.
 
Dr Ian Frayling of Cardiff University's Institute of Medical Genetics, who was involved in the international research and development of the new classification system, said: "As a result of this work, doctors will now be able to say much more confidently whether those patients have Lynch Syndrome, and therefore whether they are at a higher risk of cancer", explaining that this would allow those in genuine need to access specialist screening for the early identification and treatment of tumours, whilst also saving NHS resources by excluding those who did not need this surveillance.
 
Comment: This work is a brilliant example of the potential power of international and multidisciplinary expert collaboration to advance understanding of genetic variation and improve health care.  Developing, testing and refining such a classification scheme based on available data is a massive and painstaking task, but will undoubtedly prove highly valuable. UK guidelines on genetic testing for Lynch Syndrome are reportedly to be revised in line with the new InSiGHT system.

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