Role of the CDKN2A Locus in Patients With Multiple Primary Melanomas
Susana PuigJosep MalvehyCélia BádenasAnna RuizDolores JiménezFrancisco CuéllarA AzónUrbà GonzálezT CastelAntoni CampoyJosep Eugeni HerreroManuel Martín GonzálezJoan BrunetMontserrat Milà
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Abstract:
We have studied a consecutive case series of patients with multiple primary melanoma (MPM) for the involvement of the melanoma susceptibility loci CDKN2A and CDK4.One hundred four MPM patients (81 patients with two primary melanomas, 14 with three, five with four, one with five, two with six, and one with seven) were included.Seven different CDKN2A germline mutations were identified in 17 patients (16.3%). In total, we identified 15 CDKN2A exon 2, one exon 1alpha missense mutation, and one exon 1beta frameshift mutation. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were more frequent in patients with familial history of melanoma (35.5%) compared with patients without (8.2%), with a relative risk (RR) of 4.32 (95% CI, 1.76 to 10.64; P = .001), and in patients with more than two melanomas (39.1%) compared with patients with only two melanomas (10%) with an RR of 3.29 (95% CI, 1.7 to 6.3; P = .002). The A148T polymorphism was more frequent in patients with MPMs than in the control population (P = .05). A variant of uncertain significance, A127S, was also detected in one patient. No CDK4 mutations were identified, suggesting that it has a low impact in susceptibility to MPM.MPM patients are good candidates for CDKN2A mutational screening. These patients and some of their siblings should be included in a program of specific follow-up with total body photography and digital dermoscopy, which will result in the early detection of melanoma in this subset of high-risk patients and improve phenotypic characterization.9584 Background: Somatic mutations of the BRAF gene has been recently reported in about two thirds of patients with malignant melanoma (MM). We here defined the contribution of BRAF to melanoma susceptibility, also making a comparison with the prevalence of CDKN2A germline mutations in MM patients from different geographical areas in Italy. Methods: Using a combination of DHPLC analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 melanoma patients (211 from North Italy and 358 from South Italy) were screened for BRAF mutations. Results: Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in 4/569 (0.7%) melanoma patients. High frequency (59%) of BRAF mutations was instead observed in tumor samples from cases also undergoing germline DNA analysis; at somatic level, substitution of valine 599 was found to account for majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively-collected patients originating from South Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected. Conclusions: Our study provides a clear assessment that mutational activation of the BRAF gene is a pathogenetic event contributing to melanoma tumorigenesis at somatic level with nearly absent participation to MM predisposition at germline level. Although at lower frequency in our population, germline CDKN2A mutations have been instead demonstrated to remain the major gene involved into the melanoma susceptibility. Work was supported by Associazione Italiana Ricerca sul Cancro and Regione Autonoma Sardegna. No significant financial relationships to disclose.
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Study of BRAF mutations in melanoma and nevi from patients with germline mutation in the CDKN2A gene
10075 Background: Germline mutations in the CDKN2A tumor suppressor gene is a rare condition associated with a high risk of melanoma. Somatic activating mutations of the BRAF gene are frequently observed in cutaneous melanoma (40–60%) but their occurrence vary according to melanoma subtypes (cutaneous, vs mucosal or uveal) and are less frequent in melanoma located on chronically sun-exposed skin. It is thought that melanomas occurring in patients carrier of a CDKN2A germline mutation are associated a second inactivating genetic event in the tumor, facilitating cellular transformation by loss of function this crucial gatekeeper of the G1-S checkpoint. However, the potential role of the MAP-kinase pathway, and more precisely, the involvement of BRAF activation, in this particular population of patients, are still unknown. Thus, our objective was to evaluate the frequency of BRAF somatic mutations in melanoma and nevi developed by patients carrier of a CDKN2A germline mutation. Methods: DNA was extracted from paraffin-embedded tissues of 36 primary melanomas, 9 metastases and 20 nevi from 31 patients with CDKN2A germline mutation. Ten sporadic melanoma from patients harbouring no CDKN2A mutation were also studied as a control population. BRAF mutations were screened by direct sequencing of exon 11 and 15. Results: BRAF mutations (V599E) were found with a significantly lower frequency of 14% (5/36) in melanomas from patients with proven CDKN2A germline mutation, as compared to a frequency of 55% (5/9) in patients with no genetic predisposition (two-sided Fishers exact test, p=0.02). Frequencies of BRAF mutations in metastases and nevi from patients with CDKN2A germline mutation were 33%(3/9) and 10% (2/20) respectively. Conclusions: BRAF mutations seem to be less frequent in melanoma from patients with familial predisposition harbouring CDKN2A germ line mutation than in sporadic melanoma. These results suggest that CDKN2A loss of function gives rise to tumorigenic pathways where genetic events distinct from BRAF activating mutation can induce cell transformation. Additional biological studies are performed on this rare population of melanoma samples in order to better characterize the specificity of cellular transformation in the context of CDKN2A germ line mutation. No significant financial relationships to disclose.
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Abstract We identified two new mutations in 2 white patients with muscle lactate dehydrogenase deficiency. Both patients had exercise intolerance, cramps, and recurrent myoglobinuria. One patient was homozygous for a 2‐bp deletion in exon 5, resulting in a frameshift with premature termination of translation. The second patient was homozygous for a G → A substitution at the 3′ end of exon 2, leading to exon skipping and splicing of exon 1 to exon 3; the aberrantly spliced messenger RNA contains a frameshift, resulting in premature termination of translation. The present report provides evidence of molecular genetic heterogeneity in white patients with muscle lactate dehydrogenase deficiency.
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9584 Background: Somatic mutations of the BRAF gene has been recently reported in about two thirds of patients with malignant melanoma (MM). We here defined the contribution of BRAF to melanoma susceptibility, also making a comparison with the prevalence of CDKN2A germline mutations in MM patients from different geographical areas in Italy. Methods: Using a combination of DHPLC analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 melanoma patients (211 from North Italy and 358 from South Italy) were screened for BRAF mutations. Results: Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in 4/569 (0.7%) melanoma patients. High frequency (59%) of BRAF mutations was instead observed in tumor samples from cases also undergoing germline DNA analysis; at somatic level, substitution of valine 599 was found to account for majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively-collected patients originating from South Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected. Conclusions: Our study provides a clear assessment that mutational activation of the BRAF gene is a pathogenetic event contributing to melanoma tumorigenesis at somatic level with nearly absent participation to MM predisposition at germline level. Although at lower frequency in our population, germline CDKN2A mutations have been instead demonstrated to remain the major gene involved into the melanoma susceptibility. Work was supported by Associazione Italiana Ricerca sul Cancro and Regione Autonoma Sardegna. No significant financial relationships to disclose.
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Abstract Motivation: Cancer researchers seeking immunotherapy targets in cancer cells need tools to locate highly expressed proteins unique to cancer cells. Missense mutation and frameshift location reporter (MMuFLR), a Galaxy-based workflow, analyzes next-generation sequencing paired read RNA-seq output to reliably identify small frameshift mutations and missense mutations in highly expressed protein-coding genes. MMuFLR ignores known SNPs, low quality reads and poly-A/T sequences. For each frameshift and missense mutation identified, MMuFLR provides the location and sequence of the amino acid substitutions in the novel protein candidates for direct input into epitope evaluation tools. Availability: http://toolshed.g2.bx.psu.edu/ Contact: rath0096@umn.edu or johns198@umn.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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Background CDKN2A has been identified as a high penetrance melanoma susceptibility gene based on the presence of germline mutations in up to 25% of melanoma – prone families (FM) and in 15% of patients with multiple primary melanoma (MPM). The CDK4 gene represents an additional melanoma susceptibility locus, with activating mutations reported in a few families worldwide. Aim To investigate the CDKN2A and CDK4 genes for germline mutations in Greek patients with cutaneous melanoma. Methods We studied all melanoma cases diagnosed in a 5-year period at a melanoma referral center in Athens, Greece. Blood samples were collected and direct sequencing of the CDKN2A exons 1α, 1β, and 2 and of exon 2 of the CDK4 gene was performed. Results Three hundred fifty eight patients were diagnosed with invasive melanoma, including 16 patients belonging to 14 families with familial melanoma (3.9% of all cases) and 10 patients with MPM (2.8% of all cases). Two of the familial cases had multiple primaries as well. Genetic screening was done in 298 patients including 9 patients with FM and 7 patients with MPM. Overall, we detected germline CDKN2A mutations in 13 out of the 298 patetients (4.4%). Two of the 14 mutation carriers, were FM cases (2/9, 22.2%), and 4 had MPM (4/7, 57%). One familial case positive for CDKN2A mutation had MPM as well. The mutation rate of sporadic melanoma cases was 2.5% (7/282). The mutations detected included 4 missence mutations (R24P-8 cases, G101R-1 patient, G101E – 1 case, R87W- 1 case), a single Trp110Stop alteration and a novel C.41_43 deletion and insertion 20bp mutation in exon 1a. We also detected the G>T alteration at position -34 in the 5′UTR in one case. The A148 T polymorphism was detected in 24 patients (8%). Finally, an R24H substitution of the CDK4 gene was detected in 1 patient with FM and MPM. Conclusions Our results show that in the greek population, CDKN2A mutations occur more frequently in genetically predisposed groups as well as in sporadic melanoma cases compared to previously reported data. We showed a low rate of familial/multiple primary melanoma cases, but a higher than expected prevalence of CDKN2A/CDK4 mutations in these cases, suggesting a stronger influence of genetic mutations on melanoma-prone individuals in countries with a low incidence rate of the disease.
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This corrigendum corrects the following article. In the article "Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III. Am J Med Genet Part A. 2020;182A:1190–1200", the authors would like to state that there are two typos that should be corrected in their article and are requesting an addition of a corrigendum to the manuscript. The following errors should be corrected: 1. The variation identified in case no 56 should be c.4098T>G, instead of c.4099T>G in Table 1 on pages 1192–1193, and in the section 3.2.2 novel variants on page 1195. Group1 Variants (frameshift, nonsense, splice site) G1 IIIa c.3526A>T p.Lys1176* Nonsense G47 IIIa G3§ IIIa c.1632dupG p.Asn545Glufs*11 Frame shift G3C§ IIIa G4 IIIa c.1735 + 1G>T Splice variant G9 IIIa c.3755delA p.Asn1252Ilefs*38 Frame shift G26 IIIa G14 IIIa G36 IIIa c.2362_2392 dup31 p.Gly798Alafs*3 Frame shift G37 IIIa c.428G>A p.Trp143* Nonsense G56 IIIa G69 IIIa Group2 variants (missense and compound heterozygous) c.1880A>G p.Asp627Gly Missense c.4331A>G p.Asn1444Ser Missense c.3069G>A, p.Trp1023* Nonsense/ c.4353G>T p.Trp1451Cys Missense c.3083 + 1G>A splice variant c.2362_2392dup31 p.Gly798Alafs*3 Frameshift/ c.3444C>G p.Tyr1148* Nonsense c.4334A>G p.Tyr1445Cys Missense/ c.3444C>G, pTyr1148* Nonsense c.2362_2392dup31 p.Gly798Alafs*3 Frameshift/ c.4334A>G p.Tyr1445Cys Missense 2. Similarly, the second change in the siblings Case nos. G61 and G61C should be c.3444C>G instead of c.3444A>G in Table 1 on pages 1192–1193.
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