Statistics from Altmetric.com
- AIF, allelic imbalance factor
- FAMMM, familial atypical multiple mole melanoma
- LOH, loss of heterozygosity
- OSCC, oral squamous cell carcinomas
Familial atypical multiple mole melanoma (FAMMM; OMIM #155601) is characterised by the familial occurrence of melanoma of the skin in combination with multiple atypical precursor naevi.1–4 The disease is inherited as an autosomal dominant trait, with germline mutations in the p16 (CDKN2A) gene having been reported in at least a quarter of FAMMM families. Previously, we reported an increased risk of pancreatic carcinoma in Dutch FAMMM families with a 19 bp deletion in exon 2 of the CDKN2A/p16 gene (p16-Leiden; OMIM #600160.0003).4
Recently a patient with three carcinomas of the pharynx and oral cavity with a germline heterozygous p16-Leiden mutation was reported.5 All three tumours showed inactivation of the retained wild type allele, with the somatic event being aberrant promoter methylation. Two other reports also described the occurrence of head and neck or oral squamous cell carcinomas (OSCC) in families with different p16 germline mutations.6,7 A relationship between p16 germline mutations and breast cancer has also been suggested, although in the families studied, BRCA1 and BRCA2 mutations were not excluded.8,9
We studied a FAMMM family (EMC13769; fig 1) with co-segregation of the p16-Leiden germline mutation, with an extraordinary number of tumours comprising OSCCs, lung tumours, breast carcinomas, and colorectal carcinomas. We determined the mutation status in the various patients and investigated by loss of heterozygosity (LOH) analysis of the wild type allele in the tumours, in combination with immunohistochemistry, whether a causal relationship exists between the p16-Leiden mutation and the development of the different tumour type. Insufficient tissue was available for methylation studies. We additionally studied four breast tumours and four lung tumours from eight other patients (from seven other families), all of whom carried a germline p16-Leiden mutation.
The first two authors contributed equally to this work.