Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non‐<i>CDKN2A/CDK4</i> melanoma families

Potjer, Thomas P.; Bollen, Sander; Grimbergen, Anneliese J E M; Doorn, Remco van; Gruis, Nelleke A.; Asperen, Christi J. van; Hes, Frederik J.; Stoep, Nienke van der

doi:10.1002/ijc.31984

Cited by 35 publications

(36 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The p.V443I variant has been previously observed in OCA patients with PWS or AS (Hutton & Spritz, ; Lee et al, ), compound heterozygous individuals with OCA2 (Lasseaux et al, ) and in an unrelated CM family in the UK (Hawkes et al, ). Additionally, the pathogenic p.N489D and p.V443I variants, among other rare OCA2 variants not present in our cohort, were reported in a Dutch CM family cohort, providing further evidence of the role of OCA2 as a CM medium penetrance or modifier susceptibility gene (Potjer et al, ).…”

Section: Heterozygous Germline Variants In Oca Genes: Variants In Ocasupporting

confidence: 78%

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Nathan

Johansson

Palmer

et al. 2019

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next‐generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four‐case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM.

show abstract

Section: Heterozygous Germline Variants In Oca Genes: Variants In Ocasupporting

confidence: 78%

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Nathan

Johansson

Palmer

et al. 2019

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

show abstract

“…In co-segregation analysis of the extended pedigree, both of these OCA2 deleterious alleles were analyzed as melanoma risk variants, with an OR of 6.55. In a recent report of a multi-gene panel screening of Dutch non-CDKN2A/CDK4 melanoma families, 9 rare pathogenic variants of OCA2 were found [65]. The p.V443I and p.N489D alleles were detected at double the frequency of Dutch GoNL reference database controls (1.8% and 0.71%) similar to the frequency of these alleles in all melanoma cases reported here (1.81% and 0.09%, S1 Table).…”

Section: Plos Onesupporting

confidence: 78%

“…However, the frequency of the p.N489D allele did not statistically differ according to disease status in the BNMS cohort. Notably, a p.V443I homozygous Dutch patient was reported as having 3 primary melanomas, as was another individual who was biallelic for OCA2 [65]. In another recent study of Australian and Danish melanoma families [66], the OCA2 p.V443I frequency was increased in cases (6 carriers in 107 cases, crude allele frequency 2.8%) and the OCA2 p.N489D was detected in three cases from one pedigree (1.4%).…”

Section: Plos Onementioning

confidence: 96%

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants

et al. 2020

View full text Add to dashboard Cite

Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin. This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls. Exome sequencing was available for 28 individuals with amelanotic/ hypomelanotic melanoma and 303 individuals with pigmented melanoma, which were compared to whole exome data from 1144 Australian controls. Microarray genotyping was available for a further 17 amelanotic/hypomelanotic melanoma, 86 pigmented melanoma, 147 melanoma cases (pigmentation unknown) and 652 unaffected controls. Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088). The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X 2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X 2 P = 0.007). No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls. Variants in TYR and OCA2 may play a role in amelanotic/ hypomelanotic melanoma susceptibility. We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.

show abstract

“…The increased risk of only one or a few tumour types is common in monogenic tumour predisposition syndromes 48. Furthermore, the absence of any NEK11 mutation in 488 Dutch familial melanoma cases49 warrants screening for NEK11 mutations in melanoma families worldwide in order to confirm the importance of NEK11 as a melanoma-susceptibility gene.…”

Section: Discussionmentioning

confidence: 99%

NEK11 as a candidate high-penetrance melanoma susceptibility gene

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non‐CDKN2A/CDK4 melanoma families

Cited by 35 publications

References 49 publications

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants

NEK11 as a candidate high-penetrance melanoma susceptibility gene

Contact Info

Product

Resources

About