Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents (original) (raw)
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Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma
Familial cancer, 2014
Approximately 10 % of all cutaneous melanoma cases occur in a familial context. The major susceptibility gene for familial melanoma is CDKN2A. In Latin America, genetic studies investigating melanoma predisposition are scarce. The aim of this work was to investigate germline CDKN2A point mutations and genomic rearrangements in a cohort of 59 Brazilian melanoma-prone patients. Screening of CDKN2A alterations was performed by sequencing and multiplex ligation probe amplification. Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions. Although this study adds to the literature on melanoma susceptibility in Latin America, it is limited by the small size of the cohort. Our findings suggest that stringent inclusion criteria led to a substantially increased rate of CDKN2A mutation de...
CDKN2A mutations in melanoma families from Uruguay
British Journal of Dermatology, 2009
Background Familial melanoma, a cluster of several cases within a single family, accounts for approximately 10% of cases of melanoma. Hereditary melanoma is defined as two or more first-degree relatives having melanoma. A member of a melanoma-prone family has a 35-70-fold increased relative risk of developing a melanoma. Genetic susceptibility is linked to the major susceptibility genes CDKN2A and CDK4, and the minor susceptibility gene MC1R. Objectives To determine the clinical and genetic characteristics of cutaneous melanoma in melanoma-prone families from Uruguay. Methods We studied 13 individuals from six melanoma-prone families living in Uruguay. Phenotype, familial and personal history were recorded. Molecular screening of CDKN2A and CDK4 was done by polymerase chain reaction-single strand conformational polymorphism analysis. The MC1R gene was sequenced. Results Mutations in CDKN2A were detected in five of six families: c.)34G>T, p.G101W and p.E88X. A novel germline mutation p.E88X, associated with hereditary melanoma in two unrelated families, is described. We hypothesize that a founder effect occurred probably in the Mediterranean region. No mutations in CDK4 were detected. Six different MC1R variants, all previously reported, were present in Uruguayan families. Conclusions The overall rate of deleterious CDKN2A mutations in our familial melanoma pedigrees, even though the sample size is small, was considerably higher (83%) than the often quoted range.
CDKN2A Germline Mutations in Individuals with Cutaneous Malignant Melanoma
Journal of Investigative Dermatology, 2007
for the GEM Study Group Cyclin-dependent kinase inhibitor type 2A (CDKN2A) has been identified as a major melanoma susceptibility gene based on the presence of germline mutations in high-risk melanoma families. In this study, we sought to identify and characterize the spectrum of CDKN2A mutations affecting p16 inhibitor of cyclin-dependent kinase type 4 (INK4a) in individuals with melanoma using a population-based study design. DNA samples from 1189 individuals with incident multiple primary melanoma (MPM) and 2424 with incident single primary melanoma unselected for family history of melanoma were available for screening of CDKN2A (p16INK4a) mutations. Variants were classified for functional impact based on intragenic position, existing functional data, sequence, and structural analysis. The impact of individual mutations and functional groupings was assessed by comparing frequencies in cases of MPM versus cases with a single first primary melanoma, and by comparing the reported incidence rates in first-degree relatives. Our results show that mutations occur infrequently in these high-risk groups, and that they occur mainly in exons 1a and 2. Rare coding variants with putative functional impact are observed to increase substantially the risk of melanoma. With the exception of the variant in position À34 of CDKN2A of known functional consequence, the remaining rare variants in the non-coding region have no apparent impact on risk.
Journal of Investigative Dermatology, 2006
The genetic basis of melanoma susceptibility among Greek patients is uncharacterized. From 107 consecutive cutaneous melanoma patients, we analyzed the CDKN2A and CDK4 loci among 18 early-onset (p40 years) and two multiplex melanoma cases. Overall, we found three CDKN2A mutations (3/20; 15%), including one novel nonsense mutation (Trp110Stop) and two Arg24Pro missense alterations. There were no mutations in ARF or CDK4. CDKN2A mutations are not uncommon among Greek melanoma patients considering that none of the mutation carriers reported a family history of melanoma.
JNCI Journal of the National Cancer Institute, 1997
Background: Approximately 10% of human cutaneous melanomas occur in families in which several members are affected. The familial predisposition to this disease is often associated with dysplastic nevus syndrome, a condition in which afflicted family members have multiple dysplastic nevi (atypical moles). The chromosome region 9p21 and markers on chromosomes 1p and 6p have been linked to melanoma susceptibility. The tumor suppressor genes CDKN2A and CDKN2B have been mapped to the 9p21 region, and genetic analyses have revealed the presence of germline CDKN2A alterations in melanoma families. The reported frequencies of such alterations, however, vary among these families. Purpose: The present investigation was carried out to determine the frequencies of CDKN2A and CDKN2B germline gene mutations among members in a population-based cohort of Swedish melanoma families (i.e., melanoma kindreds). Methods: DNA was prepared from blood samples obtained from 181 individuals belonging to 100 melanoma kindreds. The polymerase chain reaction (PCR) technique, followed by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses, were used to identify the types and frequencies of mutations in exons 1, 1, 2, and 3 of the CDKN2A gene and in exons 1 and 2 of the CDKN2B gene. Results: CDKN2A gene aberrations were independently identified by both SSCP and nucleotide-sequence analyses. Nucleotide-sequence analysis identified a single point mutation leading to a substitution of leucine for proline in codon 48 of exon 1 in a family with a history of melanoma and several other cancers. A second abnormality, leading to an insertion of an extra arginine residue at codon number 113 of exon 2, was seen in four separate families. The CDKN2A exon-3 coding region had the wild-type sequence in all samples. No germline mutations were found in the alternative exon 1 of the CDKN2A gene or in exons 1 and 2 of the CDKN2B gene. Conclusions: The present investigation demonstrates that CDKN2A germline gene mutations were observed in 7.8% of the 64 Swedish melanoma kindreds that each included at least two firstdegree relatives with melanoma and dysplastic nevus syndrome. No CDKN2A exon 1 or CDKN2B mutations were identified. The critical genes responsible for the inheritance of a susceptibility to develop melanoma among family members in this population have yet to be identified. [J Natl Cancer Inst 1997;89:697-702]