Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.
dc.contributor.author | Birch, Jillian M | |
dc.contributor.author | Blair, Val | |
dc.contributor.author | Kelsey, Anna M | |
dc.contributor.author | Evans, D Gareth R | |
dc.contributor.author | Harris, Martin | |
dc.contributor.author | Tricker, K J | |
dc.contributor.author | Varley, Jennifer | |
dc.date.accessioned | 2010-02-12T16:31:34Z | |
dc.date.available | 2010-02-12T16:31:34Z | |
dc.date.issued | 1998-09-03 | |
dc.identifier.citation | Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. 1998, 17 (9):1061-8 Oncogene | en |
dc.identifier.issn | 0950-9232 | |
dc.identifier.pmid | 9764816 | |
dc.identifier.doi | 10.1038/sj.onc.1202033 | |
dc.identifier.uri | http://hdl.handle.net/10541/92046 | |
dc.description.abstract | The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations. | |
dc.language.iso | en | en |
dc.subject | Tumour Suppressor Protein p53 | en |
dc.subject | Cancer | en |
dc.subject.mesh | Adolescent | |
dc.subject.mesh | Adult | |
dc.subject.mesh | Age Factors | |
dc.subject.mesh | Aged | |
dc.subject.mesh | Aged, 80 and over | |
dc.subject.mesh | Chi-Square Distribution | |
dc.subject.mesh | Child | |
dc.subject.mesh | Child, Preschool | |
dc.subject.mesh | Cohort Studies | |
dc.subject.mesh | DNA Mutational Analysis | |
dc.subject.mesh | Family | |
dc.subject.mesh | Family Health | |
dc.subject.mesh | Female | |
dc.subject.mesh | Genotype | |
dc.subject.mesh | Germ-Line Mutation | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Infant | |
dc.subject.mesh | Infant, Newborn | |
dc.subject.mesh | Li-Fraumeni Syndrome | |
dc.subject.mesh | Male | |
dc.subject.mesh | Middle Aged | |
dc.subject.mesh | Neoplasms | |
dc.subject.mesh | Pedigree | |
dc.subject.mesh | Phenotype | |
dc.subject.mesh | Tumor Suppressor Protein p53 | |
dc.title | Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. | en |
dc.type | Article | en |
dc.contributor.department | CRC Paediatric and Familial Cancer Research Group and Department of Histopathology, Royal Manchester Children's Hospital, UK. | en |
dc.identifier.journal | Oncogene | en |
html.description.abstract | The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations. |