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Rare variant increases risk to familial and sporadic melanoma

Analysis of a study published in a science journal   |   By Dr Gurdeep Sagoo   |   Published 25 November 2011
Study: A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.
By: Yokoyama S. et al. (47 authors total)
In: Nature
Link: http://dx.doi.org/10.1038/nature10630
What this study set out to do:

To identify novel rare melanoma risk variants using whole genome sequencing.

How they went about it:

The researchers conducted whole genome sequencing of a single melanoma patient from a family with multiple melanoma cases previously shown not to carry two known familial melanoma mutations (CDKN2A and CDK4). The E318K variant in the MITF gene was prioritised as an attractive candidate gene for follow up in the remaining family members. Replication was sought in two large Australian case-control and two population-based studies from the UK. Additional lab work was also conducted to identify the functional significance of the identified variant.

Outcome:

The MITF gene variant E318K was identified as a medium-penetrance melanoma risk variant. Both the Australian and UK case-control studies showed the variant was rare (1-2%) in the population, but increased risk of sporadic melanoma. Additional analyses suggest that some of the risk identified by MITF E318K may be attributable to nevus count and non-blue eye colour with no association to other risk factors such as skin colour, hair colour or freckling.

Conclusion:

This mutation was identified in several melanoma families and also in the general population. The use of whole genome sequencing in appropriate affected individuals allows the identification of novel rare risk variants that would not normally be identifiable through either genome-wide association studies or traditional family-based linkage approaches.

Our view:

This is another example of how whole genome sequencing is being used to identify novel rare disease-risk variants. With only a small fraction of inherited melanoma disease risk identified thus far, this approach shows great promise in uncovering those variants that genome-wide linkage and association are unable to detect. This publication is sure to be the first of many with the researchers stating that this work is “part of a larger sequencing effort to identify novel melanoma risk genes” - although how findings may translate into clinical practice remains to be seen, potentially including routine skin cancer screening for those at increased risk.

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