Cancer risks and prognosis in familial melanoma kindreds

Malignant melanoma of the skin is one of the most rapidly increasing cancers in many western countries, including Sweden. This incidence rise is mainly attributed to sun-seeking habits with increased intermittent UVR exposure, a major risk factor for melanoma. Family history is another important risk factor for melanoma, approximately 10% of all cases occur in melanoma families. Germline mutations in the tumor suppressor gene CDKN2A occur in 5–25% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. Individuals with p.Arg112dup and several other CDKN2A mutations also have an increased risk of developing pancreatic carcinoma, but less has been known about carriers’ risks of other cancers. High-risk melanoma associated mutations, other than CDKN2A have yet only been identified in a small number of families, in the majority of melanoma families, the cause for heredity still remains unsolved. So far, there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. Also research addressing survival functions in melanoma families have until now been lacking. Compared to cutaneous melanoma, uveal melanoma is a much rarer disease, where no incidence rise or any strong association with UVR exposure has been observed. Familial uveal melanoma cases exist, but are rare. Until 2-3 years ago, there was no germline gene mutation known to be associated with uveal melanoma.



In papers I-III cancer risks and prognosis in familial melanoma kindreds, depending on CDKN2A mutation status is estimated by linkage of personal identity numbers of familial melanoma kindreds to several Swedish Registries, including the Multi-generation Registry and the Cancer Registry. Paper IV is a family-based association study employing whole-exome sequencing to identify a disease associated mutation in a rare uveal melanoma family.



Carriers of the Swedish founder mutation in CDKN2A and also carriers’ un-genotyped first- and second-degree relatives were found to have significantly increased risks of melanoma, pancreatic cancer, and cancers in respiratory and upper digestive tissues. Ever-smoking carriers had, compared to never-smoking carriers, significantly higher risks of these non-melanoma cancers. Familial melanoma cases with no CDKN2A mutation and their first-degree relatives had significant increased risk of melanoma and of sqaumous cell skin cancer, but not of other cancers. CDKN2A mutated melanoma cases had compared to CDKN2A wt cases, after adjusting for age, sex and tumor thickness, significantly increased mortality from melanoma and from non-melanoma cancers. Compared to matched sporadic melanoma cases, CDKN2A mutated cases had significantly increased mortality from both melanoma and non-melanoma cancers, while CDKN2A wt cases had no mortality increase compared to sporadic cases. In the uveal melanoma family, a disease segregating mutation was found in the BAP1 tumor suppressor gene on chromosome 3p21.



These studies demonstrate different risk spectra among familial melanoma kindreds. CDKN2A mutation carriers have besides from melanoma high risks of tobacco-related cancers and have worse survival from both melanoma and other cancers compared to non-carriers. Familial melanoma cases with no CDKN2A mutation have increased risks only of skin cancers and have survival comparable to sporadic melanoma cases. BAP1 mutation carriers have high risks of uveal melanoma and also of cutaneous melanoma and of other cancers. These findings further justify CDKN2A mutation testing of melanoma family members in the clinical setting where the mutation status should determine the follow-up routines in affected families. Members of CDKN2A wt melanoma families require counseling and screening aimed at prevention and earlier detection of skin cancers while CDKN2A mutation carriers require in addition to dermatologic surveillance, follow-up for non-skin cancers and also close follow-up for melanoma recurrences. BAP1 mutation carriers require ophthalmologic, oncologic and dermatologic surveillance