Eirini Christodoulou 1 , Remco van Doorn 2 , Mijke Visser 2 , Amina Teunisse 3 , Mieke Versluis 4 , Pieter van der Velden 4 , Nicholas K Hayward 5 , Aart Jochemsen 3 , Nelleke Gruis 2 Show Affiliations »
Abstract
BACKGROUND: A proportion of patients diagnosed with cutaneous melanoma reports a positive family history. Inherited variants in CDKN2A and several other genes have been shown to predispose to melanoma; however, the genetic basis of familial melanoma remains unknown in most cases. The objective of this study was to provide insight into the genetic basis of familial melanoma. METHODS: In order to identify novel melanoma susceptibility genes, whole exome sequencing (WES) analysis was applied in a Dutch family with melanoma. The causality of a candidate variant was characterised by performing cosegregation analysis in five affected family members using patient-derived tissues and digital droplet PCR analysis to accurately quantify mutant allele frequency. Functional in-vitro studies were performed to assess the pathogenicity of the candidate variant. RESULTS: Application of WES identified a rare, nonsense variant in the NEK11 gene (c.1120C>T, p.Arg374Ter), cosegregating in all five affected members of a Dutch family. NEK11 (NIMA-related Kinase 11) is involved in the DNA damage response, enforcing the G2/M cell cycle checkpoint. In a melanoma from a variant carrier, somatic loss of the wildtype allele of this putative tumour suppressor gene was demonstrated. Functional analyses showed that the NEK11 p.Arg374Ter mutation results in strongly reduced expression of the truncated protein caused by proteasomal degradation. CONCLUSION: The NEK11 p.Arg374Ter variant identified in this family leads to loss-of-function through protein instability. Collectively, these findings support NEK11 as a melanoma susceptibility gene. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
BACKGROUND: A proportion of patients diagnosed with cutaneous melanoma reports a positive family history. Inherited variants in CDKN2A and several other genes have been shown to predispose to melanoma ; however, the genetic basis of familial melanoma remains unknown in most cases. The objective of this study was to provide insight into the genetic basis of familial melanoma . METHODS: In order to identify novel melanoma susceptibility genes, whole exome sequencing (WES) analysis was applied in a Dutch family with melanoma . The causality of a candidate variant was characterised by performing cosegregation analysis in five affected family members using patient -derived tissues and digital droplet PCR analysis to accurately quantify mutant allele frequency. Functional in-vitro studies were performed to assess the pathogenicity of the candidate variant. RESULTS: Application of WES identified a rare, nonsense variant in the NEK11 gene (c.1120C>T, p.Arg374Ter), cosegregating in all five affected members of a Dutch family. NEK11 (NIMA-related Kinase 11 ) is involved in the DNA damage response, enforcing the G2/M cell cycle checkpoint. In a melanoma from a variant carrier, somatic loss of the wildtype allele of this putative tumour suppressor gene was demonstrated. Functional analyses showed that the NEK11 p.Arg374Ter mutation results in strongly reduced expression of the truncated protein caused by proteasomal degradation. CONCLUSION: The NEK11 p.Arg374Ter variant identified in this family leads to loss-of-function through protein instability. Collectively, these findings support NEK11 as a melanoma susceptibility gene. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Entities: Disease
Gene
Mutation
Species
Keywords:
cancer: dermatological; genetics; molecular genetics
Mesh： See more »
Substances： See more »
Year: 2019
PMID： 31704778 DOI： 10.1136/jmedgenet-2019-106134
Source DB: PubMed Journal: J Med Genet ISSN： 0022-2593 Impact factor: 6.318