Abstract
Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected POT1 and CHEK2 variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; p = 2.0 × 10−6). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (CDKN2A, POT1, ACD) and 22 (8.3%) patients in other cancer syndrome genes (NBN, BRCA1/2, CHEK2, ATM, WRN, RB1). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6–413.1; p = 3.2 × 10−7) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4–3.8; p = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2–6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers.
Highlights
With 287,723 newly diagnosed cases and 60,712 fatalities in 2018, cutaneous melanoma remains the deadliest skin malignity globally
We identified medium-size indels using Pindel and copy number variations (CNV) using CNVkit, using the settings that we described in detail recently [26,27]
Hereditary melanoma risk was not increased in carriers of low-risk gene mutations (Table 4); we found a higher frequency in patients vs. controls for mutations in TYRP1 (0.8 vs. 0%; p = 0.02) and OCA2
Summary
With 287,723 newly diagnosed cases and 60,712 fatalities in 2018, cutaneous melanoma remains the deadliest skin malignity globally. The highest standardized melanoma incidence occurs in Australia and New Zealand; European and US patients account for more than 75% of new melanoma cases annually [1]. The GLOBOCAN cancer registry ranks the Czech Republic as 18th among 185 countries in the world in terms of age-standardized melanoma incidence rates (between the USA and Canada) [2]. Other individual host factors include the amount, type, and arrangement of cutaneous melanin, the presence of multiple atypical moles (the most frequent precancerous melanoma lesions), and a family history of melanoma [4]. The hereditary component of melanoma development has been assessed in a large prospective study of twins from Nordic countries revealing melanoma heritability with a familial cancer risk of 19.6% and 6.1% for monozygotic and dizygotic twins, respectively, compared with 1.2% for the overall population [5]. The proportion of familial melanoma cases is approximately 5–10%; pathogenic germline mutation carriers have been identified in only a minority of the analyzed familial melanoma cases [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
