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

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations

Background: Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. Methods: CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. Results: Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). Conclusion: Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations

Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated

Genetic insight into sick sinus syndrome

Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS

Personalized Medicine in Malignant Melanoma: Towards Patient Tailored Treatment

Despite enormous international efforts, skin melanoma is still a major clinical challenge. Melanoma takes a top place among the most common cancer types and it has one of the most rapidly increasing incidences in many countries around the world. Until recent years, there have been limited options for effective systemic treatment of disseminated melanoma. However, lately, we have experienced a rapid advancement in the understanding of the biology and molecular background of the disease. This has led to new molecular classifications and the development of more effective targeted therapies adapted to distinct melanoma subtypes. Not only are these treatments more effective but they can be rationally prescribed to the patients standing to benefit. As such, melanoma management has now become one of the most developed for personalized medicine. The aim of the present paper is to summarize the current knowledge on melanoma molecular classification, predictive markers, combination therapies, as well as emerging new treatments

Ökad kunskap om familjärt melanom och de bakomliggande generna

Approximately 5-10 % of all melanoma patients have close relatives with melanoma. 5-20% of melanoma families have germline mutations in the CDKN2A gene. Swedish CDKN2A mutation carriers have a young median age of onset of melanoma, increased risks of multiple primary melanoma and of tobacco-associated cancers in respiratory and upper digestive tissues, and also worse survival compared to non-carriers. In up to 80% of melanoma families no high risk melanoma associated germline mutations are found. In a few (non-Swedish) melanoma families, mutations in other genes have been found, including CDK4, TERT, POT1, ACD and TERF2IP. In some families with multiple cases of uveal and cutaneous melanoma (including a few Swedish families), mutations in the BAP1 gene have been found. In genes that regulate cellular pigmentation pathways, including MC1R, ASIP, IRF4, TYR, TYRP1 and OCA, there are different common variants that determine complexion traits, and those variants are also associated with different risks of melanoma. Members belonging to identified melanoma families require close follow-up with dermatologic exams. Individuals with known mutations in tumor suppressor genes such as CDKN2A and BAP1 require, in addition, follow up for other cancers

Cancer risks and survival in patients with multiple primary melanomas : Association with family history of melanoma and germline CDKN2A mutation status

Background Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas. Objective We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes. Methods Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries. Results Familial MPM cases with germline CDKN2A mutations were youngest at the diagnosis of their second melanoma (median age 42 years) and had among the MPM cohorts the highest relative risks (RR) compared to controls of developing >2 melanomas (RR 238.4, 95% CI 74.8-759.9). CDKN2A mutated MPM cases and their first-degree relatives were the only cohorts with increased risks of nonskin cancers compared to controls (RR 3.6, 95% CI 1.9-147.1 and RR 3.2, 95% CI 1.9-5.6, respectively). In addition, CDKN2A mutated MPM cases had worse survival compared with both cases with familial (HR 3.0, 95% CI 1.3-8.1) and sporadic wild-type MPM (HR 2.63, 95% CI 1.3-5.4). Limitations Our study examined outcomes in subgroups of MPM patients, which affected the sample size of the study groups. Conclusion This study demonstrates that CDKN2A mutation status and family history of melanoma significantly affects outcomes of MPM patients

Familial features affecting the melanoma risk in <i>CDKN2A</i>-negative melanoma families: a study based on the Swedish Cancer Registry

Familial features affecting the melanoma risk in CDKN2A-negative melanoma families: a study based on the Swedish Cancer Registr