No abstract

SummaryThe family history of cancer in children treated for a solid malignant tumour in the Paediatric Oncology Department at Institute Gustave-Roussy, has been investigated. In order to determine the role of germline p53 mutations in genetic predisposition to childhood cancer, germline p53 mutations were sought in individuals with at least one relative (first-or second-degree relative or first cousin) affected by any cancer before 46 years of age, or affected by multiple cancers. Screening for germline p53 mutation was possible in 268 index cases among individuals fulfilling selection criteria. Seventeen (6.3%) mutations were identified, of which 13 were inherited and four were de novo. Using maximum likelihood methods that incorporate retrospective family data and correct for ascertainment bias, the lifetime risk of cancer for mutation carriers was estimated to be 73% for males and nearly 100% for females with a high risk of breast cancer accounting for the difference. The risk of cancer associated with such mutations is very high and no evidence of low penetrance mutation was found. These mutations are frequently inherited but de novo mutations are not rare. 1932-1937 © 2000 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1167, available online at http://www.idealibrary.com on family members, previously informed by the proband's parents, were contacted for a telephone interview. Information on relatives included general characteristics (sex, date of birth, malformations, date and cause of death) and the occurrence of any cancer. When cancers had occurred, confirmation of the diagnoses and age at onset were sought in medical and pathology records. Only invasive cancers were considered, excluding non-melanoma skin cancer and in situ carcinoma. Informed consent was obtained from parents before inclusion in the study.A subgroup of children with a putative increased frequency of susceptibility genes, was defined on the basis of the occurrence of either of the following criteria: (i) at least one cancer case affecting a first-or second-degree relative or a first cousin before the age of 46 ('familial cases'), (ii) multiple primary cancers in the proband regardless of their family history ('multiple tumour cases').Blood samples were obtained from the proband, his/her parents and, when a relative was affected, from all the available family members in that branch of the pedigree. Specific informed consent for blood sampling was obtained from all participating relatives. This study received the approval at the local ethics committee (CCPPRB, Kremlin-Bicêtre). Genotyping p53p53 was genotyped in peripheral lymphocytes isolated from fresh blood samples. Direct sequencing was used for the first set of 100 samples. Genomic DNA was amplified as three fragments including respectively exons 2-4, exons 5-8 and exons 9-11. Polymerase chain reaction (PCR) primers sequences are available on request. Genotyping was subsequently carried out with a functional assay in yeast (FASAY), as described by Ishioka et al, (1993), and modi...

No abstract