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.
- cancer: dermatological
- molecular genetics
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AJ and NG are joint senior authors.
Contributors RvD and NG formulated research goals and aims. WES analysis was performed by NKH. Experiments were performed by EC, MVi, AT, MVe. PadV supervised Digital PCR analyses. AJ supervised functional analyses in cell lines. Statistical analysis was performed by EC. Overall progress was supervised by RvD, AJ and NG.
Funding This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 641458. Mijke Visser and Nick Hayward were supported by grant from the Dutch Cancer Society (UL2012-5489) and the National Health and Medical Research Council of Australia, respectively.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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