title: Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 x 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 x 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.
authors.affiliation: Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, APHP, IFR02, Université Paris, Henri Huchard, 75018 Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Di Lucca
authors.forename: Mickael
authors.initials: M
authors.lastname: Guedj
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lacapère
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Fargnoli
authors.forename: Agnes
authors.initials: A
authors.lastname: Bourillon
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupin
authors.forename: Pierre
authors.initials: P
authors.lastname: Wolkenstein
authors.forename: Philippe
authors.initials: P
authors.lastname: Aegerter
authors.forename: Philippe
authors.initials: P
authors.lastname: Saiag
authors.forename: Vincent
authors.initials: V
authors.lastname: Descamps
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.forename: Ketty
authors.initials: K
authors.lastname: Peris
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Nadem
authors.initials: N
authors.lastname: Soufir
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004260:DNA Repair / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004812:Epidemiologic Methods; D005260:Female; D005602:France / Q000453:epidemiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006200:Hair Color / Q000235:genetics; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D012880:Skin Pigmentation / Q000235:genetics; D013471:Sunburn / Q000150:complications / Q000453:epidemiology; D014466:Ultraviolet Rays / Q000009:adverse effects; D044465:White People / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D055815:Young Adult; D000099270:Y-Family DNA Polymerases
chemical_list: D004259:DNA-Directed DNA Polymerase; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases