Get access

Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum-Variant Patients Reveals 12 New Disease-Causing POLH Mutations

Authors

  • Kristina Opletalova,

    1. Laboratory of Genetic Stability and Oncogenesis, UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France
    2. Department of Dermatology, Institut Gustave Roussy, Villejuif, France
    Search for more papers by this author
    • These authors are considered as the joint first coauthors.

  • Agnès Bourillon,

    1. Laboratoire de Génétique, Hôpital Bichat, APHP, Paris, France
    Search for more papers by this author
    • These authors are considered as the joint first coauthors.

  • Wei Yang,

    1. Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Caroline Pouvelle,

    1. Laboratory of Genetic Stability and Oncogenesis, UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France
    2. Equipe labellisée Ligue Contre le Cancer “TLS polymerases and cancer”, University Paris-Sud and Institut de Cancérologie Gustave Roussy, Villejuif, France
    Search for more papers by this author
  • Jacques Armier,

    1. Laboratory of Genetic Stability and Oncogenesis, UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France
    Search for more papers by this author
  • Emmanuelle Despras,

    1. Laboratory of Genetic Stability and Oncogenesis, UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France
    2. Equipe labellisée Ligue Contre le Cancer “TLS polymerases and cancer”, University Paris-Sud and Institut de Cancérologie Gustave Roussy, Villejuif, France
    Search for more papers by this author
  • Ludovic Martin,

    1. Service de Dermatologie, CHU Angers, Angers, France
    Search for more papers by this author
  • Christine Mateus,

    1. Department of Dermatology, Institut Gustave Roussy, Villejuif, France
    Search for more papers by this author
  • Caroline Robert,

    1. Department of Dermatology, Institut Gustave Roussy, Villejuif, France
    Search for more papers by this author
  • Patricia Kannouche,

    1. Laboratory of Genetic Stability and Oncogenesis, UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France
    2. Equipe labellisée Ligue Contre le Cancer “TLS polymerases and cancer”, University Paris-Sud and Institut de Cancérologie Gustave Roussy, Villejuif, France
    Search for more papers by this author
  • Nadem Soufir,

    1. Laboratoire de Génétique, Hôpital Bichat, APHP, Paris, France
    2. Inserm U976, Centre de Recherche Sur la Peau, Hôpital Saint Louis, APHP and University Paris, Paris, France
    Search for more papers by this author
  • Alain Sarasin

    Corresponding author
    1. Laboratory of Genetic Stability and Oncogenesis, UMR8200 CNRS, University Paris-Sud and Institut Gustave Roussy, Villejuif, France
    2. Department of Genetics, Institut Gustave Roussy, Villejuif, France
    • Correspondence to: Alain Sarasin, UMR8200 CNRS, Institut Gustave Roussy, PR2, 114, rue Edouard Vaillant, 94805 Villejuif, France. E-mail: alain.sarasin@gustaveroussy.fr

    Search for more papers by this author

  • Contract grant sponsors: Centre National de la Recherche Scientifique (Paris, France); the Agence Nationale pour la Recherche (Paris); the Association des Enfants de la Lune (Tercis, France); La Ligue Nationale contre le Cancer (“Equipe labellisée”), Paris, France; the Institut National du Cancer (INCa, PLBio-2010), Paris; the Agence Nationale de la Recherche (N° ANR-09-PIRI-001), Paris.

  • Communicated by Rolf H. Sijmons

ABSTRACT

Xeroderma pigmentosum variant (XP-V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP-V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV-hypersensitivity in the presence of caffeine, a signature of the XP-V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal-cell carcinoma was 13 per patient, six for squamous-cell carcinoma, and five for melanoma. XP-V is due to defects in the translesion-synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life-cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP-Vs from sun exposure.

Ancillary