Malignant melanoma-Risk factors and the CDKN2A mutation in relation to phenotypes and other cancers

Sammanfattning: Background: Cutaneous malignant melanoma (CMM) is an increasingly common cancer in fair-skinned people. The purpose of this thesis was to study high-risk patients with multiple tumours including a CMM, high-risk families with the unique Swedish germline mutation in CDKN2A(113insArg), as well as study risk factors for CMM in women. Methods: Tumours associated with CMM, in individuals/probands with four or more primary tumours including at least one CMM were genotyped. The probands were further sub-grouped according to subsequent cancers (Paper I). Possible similarities in tumour patterns were studied in their close relatives (Paper II'). Further, melanoma-prone families in southern Sweden with the 113insArg/CDKN2A mutation were phenotyped and genotyped (Paper III). Finally, a population-based cohort of originally 40.000 women was prospectively followed for 18 years regarding CMM after answering a questionnaire about CMM risk factors (Paper IV). Results: Papers I-II: The mutation was overrepresented in probands with multiple CMM. Non-mutation probands presented e.g. Neural System Tumours (NSTs), adenocarcinomas and non-melanoma skin cancer (NMSC), which were also seen in their relatives. For the relatives an overall increased risk for cancer was seen. Paper III: Positive mutation status was associated with clinically atypical nevi (CAN), and CMM diagnosis with red hair colour and CAN. No CMM were diagnosed in non-mutation carriers. The overall total nevus count (median 12, IQR: 5-25) and rate of individuals affected by CAN (14%), were lower in these families than shown in previous, population-based, Swedish studies. No atypical mole syndrome (AMS) phenotype was seen. Paper IV: Family history and ≥1 nevus on the left arm were risk factors for CMM, irrespective of age of the participants. Younger women with a history of frequent sunbed use had an additionally increased risk for CMM. CMM on the trunk were associated with a family history of CMM, a high nevus number and the youngest age at diagnosis. Conclusions: The 113insArg/CDKN2A mutation in these melanom-prone families is difficult to diagnose dermatologically, but the presence of CMM seems to be completely associated with the mutation. Hence, mutation carriers must be followed-up by dermatologists irrespective of phenotype. The population-based risks for CMM in southern Swedish women seem to be associated with a family history of CMM, a higher nevus number and, for younger women, the use of sunbeds. 'Supplement.