Genome-wide linkage scan for atypical nevi in p16-Leiden melanoma families

Snoo, Femke A. de; Hottenga, Jouke Jan; Gillanders, Elizabeth M.; Sandkuijl, Loudewijk A.; Jones, Mary Pat; Bergman, Wilma; Drift, Clasine van der; Leeuwen, Inge van; Mourik, Lenny van; Huurne, Jeanet A.C. ter; Frants, Rune R.; Willemze, Rein; Breuning, Martijn H.; Trent, Jeffrey M.; Gruis, Nelleke A.

doi:10.1038/ejhg.2008.72

Cited by 17 publications

(17 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Again, this is similar to findings in CDKN2A families 4041 The presence of clinically atypical nevi has been suggested to be a modifier of melanoma risk in CDKN2A mutation carriers,40 41 and we observed that among affected subjects, the median age at first melanoma diagnosis was 7.5 years lower in atypical nevi positive than in negative family members. On the other hand, the frequency of these nevi was similar in affected and unaffected CDK4 positive subjects (table 3).…”

Section: Discussionsupporting

confidence: 90%

Melanoma prone families withCDK4germline mutation: phenotypic profile and associations withMC1Rvariants

et al. 2013

View full text Add to dashboard Cite

BackgroundCDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype.MethodsAll known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced.ResultsEleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010).ConclusionOur study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.

show abstract

Section: Discussionsupporting

confidence: 90%

Melanoma prone families withCDK4germline mutation: phenotypic profile and associations withMC1Rvariants

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Interestingly, the association appeared to be restricted to families with CDKN2A mutations. Our results are consistent with findings from a previous genome-wide linkage scan for DN in melanoma families segregating p16-Leiden mutations, in which the strongest linkage signal for DN was mapped to chromosome 7q21.3, a region containing CDK6 (de Snoo et al , 2008). Given that the association was only seen in CDKN2A mutation positive families, it is not surprising that we did not replicate the association in other datasets that mostly included subjects negative for CDKN2A mutations.…”

Section: Discussionsupporting

confidence: 92%

Association of Genetic Variants in CDK6 and XRCC1 with the Risk of Dysplastic Nevi in Melanoma-Prone Families

Liang

Pfeiffer

et al. 2014

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each SNP separately, adjusted for age, sex, CMM and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific p-values. Two genes, CDK6 and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent datasets (random effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.

show abstract

“…Although the presence of CAN was associated with both melanoma development and a positive CDKN2A mutation status, none of all 97 participants could fulfill the AMS phenotype criteria. This is in line with the recent Dutch study about p16-Leiden founder mutation, AMS and genomewide scan for AMS genes [24].…”

Section: Discussionsupporting

confidence: 87%

“…In all examined anatomical sites, total mean number of nevi was significantly higher for mutation carriers, in correlation with other studies [12,24] and supporting that CDKN2A might probably be a nevogenic gene. Nevertheless, mean and median total naevus count in mutation carriers and in the whole cohort were lower than in previously reported population-based Swedish data [18,20].…”

Section: Discussionsupporting

confidence: 85%

Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype

Nielsen¹,

Harbst²,

Måsbäck³

et al. 2010

Melanoma Research

View full text Add to dashboard Cite

Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.

show abstract

Genome-wide linkage scan for atypical nevi in p16-Leiden melanoma families

Cited by 17 publications

References 23 publications

Melanoma prone families withCDK4germline mutation: phenotypic profile and associations withMC1Rvariants

Melanoma prone families withCDK4germline mutation: phenotypic profile and associations withMC1Rvariants

Association of Genetic Variants in CDK6 and XRCC1 with the Risk of Dysplastic Nevi in Melanoma-Prone Families

Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype

Contact Info

Product

Resources

About