NEK11 as a candidate high-penetrance melanoma susceptibility gene

Abstract

BackgroundA 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.MethodsIn 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.ResultsApplication 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.ConclusionThe 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.

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

“…Functional validation will be part of future studies that will help define the role of these variants/genes in melanoma susceptibility. Another minor limitation is that the panel did not include several rare/very rare recently proposed candidate melanoma genes such as GOLM1 (golgi membrane protein 1) [61], POLE (DNA polymerase epsilon, [62]), NEK11 [63], EBF3, OCA2, TYR, TYRP1, and SLC45A2 [26,59,[64][65][66], reviewed in [67].…”

Predictors of germline status for hereditary melanoma: 5 years of multi-gene panel testing within the Italian Melanoma Intergroup

“…[4][5][6][7][8][9][10][11][12][13] Additional genes, such as GOLM1, EBF3, POLE and NEK11, have been recently linked to melanoma susceptibility, but are not yet included in clinical genetic testing due to the lack of risk estimates. [14][15][16][17][18] A 2009 Italian Melanoma Intergroup (IMI) study established that the prevalence of CDKN2A pathogenic/likely pathogenic variant (PV/LPV) carriers was 33% in all recruited families and 25% in families with only two CM cases, concluding that clinical genetic testing in those latter families was justified in terms of the likelihood of identifying a PV. 19 In another 2016 IMI study involving multiple primary melanoma (MPM) cases, 19% of cases carried CDKN2A or, rarely, MITF variants.…”

“… 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 Additional genes, such as GOLM1 , EBF3 , POLE and NEK11, have been recently linked to melanoma susceptibility, but are not yet included in clinical genetic testing due to the lack of risk estimates. 14 , 15 , 16 , 17 , 18 …”

Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients

“…A preliminary variant analysis was performed by using QueryOR [ 34 ], a platform for variant prioritization developed at CRIBI Biotechnology Center of the University of Padova (Padova, Italy). We focused the germline analysis on a list of 113 genes ( Table S1 ) including well-established melanoma predisposing genes as well as genes reported in landmark studies of cancer predisposition [ 35 , 36 , 37 , 38 , 39 , 40 ]. Classification by COSMIC Cancer Gene Census is also provided [ 41 ].…”