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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...

Childhood predictive genetic testing for Li–Fraumeni syndrome

“…Reports by Birch et al [11] and Frebourg et al [12] reported constitutional TP53 mutations in 6 of 12 and 7 of 15 LFS families respectively, giving a proportion for recognised constitutional mutations in these families of 50%. More recently Chompret et al [13] reported mutations in 8 out of 16 LFS families. Varley et al [14] extended the series of Birch et al [11] used comprehensive, automated methods to sequence exons 1-11 and included all splice junctions, the promotor and the 3 0 -untranslated region.…”

TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset

“…The identification of these de novo germline mutations emphasizes the importance of TP53 mutation analysis in young patients with multiple malignancies that are part of the LFS spectrum or adrenocortical carcinoma irrespective of cancer history in their relatives, as suggested by the Chompret LFL criteria [7] but not by the classical LFS or other LFL criteria [5,6]. The second proband with adrenocortical carcinoma was a child of Brazilian origin presenting the p.Arg337His TP53 mutation (Table 1) previously reported as a founder mutation in southern Brazil [31][32][33] and in a single patient of Portuguese background living in France [16]. Since the proband's mother was a healthy carrier, the p.Arg337His mutation did not arise de novo and indeed it has been considered a low penetrance mutation that contributes in a tissue-specific manner to the development of adrenocortical carcinoma in childhood [34,35].…”

“…These data made possible the shift from clinical and familial criteria to genetic criteria for the definition of LFS. A significant proportion of the TP53 germline mutations occur de novo [14][15][16][17] and this contributes to the higher sensitivity of the Chompret LFL criteria to identify patients who are TP53 mutation carriers, as they allow inclusion of patients with multiple narrow spectrum LFS malignancies or with adrenocortical carcinomas irrespective of their family history of cancer [7,13].…”

A Novel <i>TP53</i> Germline Mutation in a Family with a History of Multiple Malignancies: Case Report and Review of the Literature

“…In 1990, both Malkin et al[ 3] and Srivastava et al[ 26] found associations between germline TP53 mutations and families with LFS. Numerous studies have found a similar association, although germline TP53 mutations are only found in approximately 70% of classic LFS cases with an even lower incidence in LFL or families with a history of primary LFS spectrum tumors [1, 7, 10,27,28,29,30,31]. …”

“…Since their 3 cases, there have been 17 additional cases, including this report, of primary CPC, occurring in patients with LFS/LFL, germline TP53 mutations, or both [12, 13, 15, 29,45,46,47,48,49,50]. The number of such cases may be underestimated since many reports do not distinguish between types of CNS tumors or divide CPTs into papillomas and carcinomas [1,2,3,4,5, 23, 25, 26, 51, 52].…”