Editor—The Li-Fraumeni syndrome (LFS) is a rare familial cancer syndrome that predisposes gene carriers to the development of diverse early onset malignancies, including soft tissue sarcomas, osteosarcomas, adrenocortical carcinomas, brain tumours, breast carcinomas, and leukaemia,1-3 with other cancer types occurring less frequently.4-6 Families adhering to the classical definition of the syndrome include those in which one subject, usually the proband, is diagnosed with a sarcoma before 45 years of age, and has a first degree relative with cancer before 45 years of age, and another first or second degree relative in the same parental lineage with any cancer diagnosed under 45 years of age or with sarcoma at any age.7 Families that do not meet these strict criteria are referred to as LFS-like (LFS-L).8 9

The majority of classical LFS families harbour germline mutations of the p53 tumour suppressor gene.10-12 However, in the remaining “classical” LFS families, and in most LFS-L families, no alterations inp53 have been found.8 9 This lack of an absolute phenotype:genotype concordance could be attributed to incomplete screening of the p53 gene, inactivation of the p53 protein through interaction with other cellular proteins or viruses, or defects in other genes involved inp53 mediated cell cycle regulatory pathways.

p16^INK4a is a candidate gene that could account for the cancer predisposition inp53 wild type LFS families. It is located on chromosome 9p21 and its three exons encode a 156 amino acid, 15.8 kDa protein.13 p16^INK4a is a cyclin dependent kinase inhibitor that is frequently mutated or deleted in many human cancer cell lines14-16 and some sporadic malignancies, including sarcomas, breast cancer, leukaemia, and brain tumours, which are all component tumours of LFS.17 Germlinep16^INK4a alterations are associated with familial melanoma.18-20 …