Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.
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.
Birch
J M
JM
CRC Paediatric and Familial Cancer Research Group and Department of Histopathology, Royal Manchester Children's Hospital, UK.
Blair
V
V
Kelsey
A M
AM
Evans
D G
DG
Harris
M
M
Tricker
K J
KJ
Varley
J M
JM
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005192:Family Health; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53