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Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that is associated with an inherited defect of the nucleotide excision repair pathway (NER). In this study, we investigated the involvement of XP genes in 86 XP patients belonging to 66 unrelated families, most of them consanguineous and originating from Maghreb. Sequencing analysis was performed either directly (44 probands) or after having previously characterized the involved XP gene by complementation assay (22 families). XPC and XPA mutations were respectively present in 56/66 and 8/66 probands. Strikingly, we identified the same homozygous frameshift mutation c.1643_1644delTG (p.Val548AlafsX25) in 87% of XP-C patients. Haplotype analysis showed a common founder effect for this mutation in the Mediterranean region, with an estimated age of 50 generations or 1,250 years. Among 7/8 XP-A patients, we found the previously reported nonsense homozygous XPA mutation (p.Arg228X). Six mutations—to our knowledge previously unreported—(five in XPC, one in XPA) were also identified. In conclusion, XPC appears to be the major disease-causing gene concerning xeroderma pigmentosum in North Africa. As the (p.Val548AlafsX25) XPC mutation is responsible for a huge proportion of XP cases, our data imply an obvious simplification of XP molecular diagnosis, at least in North Africa. [ABSTRACT FROM AUTHOR]

Background: The INK4a-ARF locus encodes two tumor suppressor proteins, p16(INK4a) and p14(ARF), that act through the Rb-CDK4 and p53 pathways, respectively. Data from murine models and sporadic human skin carcinomas implicate p16(INK4a) and p14(ARF) in the development of skin carcinomas. We examined the frequency of INK4a-ARF, p53, and CDK4 mutations in skin carcinomas from patients with xeroderma pigmentosum (XP), a rare autosomal disease that is associated with a defect in DNA repair and that predisposes patients to skin cancer.Methods: DNA from skin cancers of 28 unrelated XP patients was screened for mutations in p53, INK4a-ARF, and CDK4 coding exons by single-strand conformation polymorphism analysis and automated sequencing. Data were evaluated with the use of the exact unconditional test derived from Fisher's test. All statistical tests were two-sided.Results: Eight of 28 XP-associated tumors had mutations in the INK4a-ARF locus. Three XP-associated tumors had multiple mutations at this locus. In all, 13 mutations in the INK4a-ARF locus were detected in XP-associated tumors, of which seven (54%) were signature UV radiation-induced mutations, i.e., tandem CC : GG-->TT : AA transitions. p53 mutations, mostly of the type induced by UV radiation, were present in 12 tumors (43%). Statistically significant positive associations were found between the frequency of mutations in p53 and in p16(INK4a) (P =.008) and between the frequency of mutations in p53 and in p14(ARF) (P<.001). No mutations were detected within the CDK4 gene.Conclusions: We have demonstrated for the first time the occurrence of UV radiation-induced mutations in INK4a-ARF in XP-associated skin carcinomas. The simultaneous inactivation of p53 and INK4a-ARF may be linked to the genetic instability caused by XP and could be advantageous for tumor progression. [ABSTRACT FROM AUTHOR]

Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation. [ABSTRACT FROM AUTHOR]

Purpose: Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to multiple early onset skin cancers, including melanoma. XPV results from mutations of the POLH gene that encodes a DNA translesion polymerase. In this work, we tested the hypothesis that POLH variants could be associated with melanoma risk. Experimental design: A common non-synonymous POLH variant, c.1783A>G p.M595V, was genotyped in 1075 melanoma patients and in 1091 ethnic-matched controls from France. In addition, we searched for rare POLH variants by sequencing the entire coding sequence in 201 patients having a familial history of melanoma (n =123), sporadic multiple melanomas (n =65) and a melanoma associated with a skin carcinoma (n =13). Results: Overall, the c.1783G, p.595V allele was statistically associated with melanoma (respective allelic frequencies, 0.040 versus 0.022, P-value=1.17×10–3, odds ratio (OR)=1.86 [1.27–2.71]), which was further confirmed by a meta-analysis including 274 patients and 174 matched controls from Italy (P-value=7.7×10–4, OR=1.84 [1.29–2.63]). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.I272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects. Conclusions: Besides severe deficiencies in translesion synthesis which are major risks factors for skin carcinomas and melanomas, less deleterious POLH variants could act as low penetrance melanoma predisposing alleles. The ongoing identification of genetic markers implied in skin cancer predisposition could help to identify high-risk subjects as targets for clinical follow-up. Replication studies in other populations are awaited to assess these data. [Copyright &y& Elsevier]

Abstract: We report here a three generations family with nevoid basal cell carcinoma syndrome (NBCCS) in which the diagnosis was made only after a second trimester of pregnancy ultrasonography revealing fetal cranio-cerebral malformations. A mutation was subsequently characterized in the aborted fetus, as well as in the mother, sister and grand-mother as an 18bp deletion in exon 15 of the patched homologue 1 (PTCH1) gene. MC1R gene sequencing identified in two NBCCS patients affected by multiple basal cell carcinomas a functional MC1R variant, D294H, previously shown to be associated with skin cancer risk. This variant was absent in the NBCCS patient that did not develop basal cell carcinomas, suggesting that this variant could have favored the development of skin cancers, in patients carrying the PTCH1 mutation. [Copyright &y& Elsevier]