作者: Alexander Marzuka-Alcalá , Michele Jacobs Gabree , Hensin Tsao
DOI: 10.1007/978-1-62703-727-3_20
关键词: Melanoma 、 BAP1 、 Microphthalmia-associated transcription factor 、 Cancer research 、 CDKN2A 、 p14arf 、 Cell cycle 、 Hereditary Melanoma 、 Biology 、 Ocular Melanoma
摘要: Familial melanoma accounts for approximately a tenth of all cases. The most commonly known susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which transmitted in an autosomal dominant fashion and 20-50 % familial Mutated p16INK4a shows impaired capacity to inhibit cyclin D1-CDK4 complex, allowing unchecked cell cycle progression. Mutations second protein coded by CDKN2A, p14ARF, are much less common result proteasomal degradation p53 with subsequent accumulation DNA damage as progresses through without functional p53-mediated response. CDK4 that impair inhibitory interaction also increase risk but these mutations extremely rare. Genes melanin biosynthetic pathway, including MC1R MITF, have been implicated melanomagenesis. variants were traditionally thought secondary intensified UV-mediated setting absent photoprotective eumelanin. Accumulation pheomelanin, appears carcinogenic effect regardless UV exposure, may be more likely mechanism. Impaired SUMOylation E318K variant MITF results increased transcription genes confer melanocytes pro-malignant phenotype. tumor suppressor BAP1 enhance metastatic potential uveal predispose cutaneous/ocular melanoma, atypical melanocytic tumors, other internal malignancies (COMMON syndrome). Genome-wide association studies identified numerous low-risk alleles. Although several identified, assessment tools developed only hereditary CDKN2A. MelaPRO, validated model relies on Mendelian inheritance Bayesian probability theories, estimates carrier future taking into account patient's family past medical history melanoma. Genetic testing currently available Melanoma Genetics Consortium recommends offering such patients context research protocols because clinical utility uncertain.