Hereditary p16-Leiden Mutation in a Patient with Multiple Head and Neck Tumors

Abstract

Recent studies have shown that most Dutch families with atypical multiple-mole melanoma (FAMMM) have a 19bp germline deletion (p16-Leiden) in exon 2 of the p16 gene (p16 [MIM 600160]) (Gruis et al. 1995; van der Velden et al. 1999van der Velden et al. , 2001. Incomplete penetrance and variable clinical expression in p16-Leiden carriers point to the fact that other genetic mechanisms can compensate for the p16 loss of function (Gruis et al. 1995). Indeed, van der Velden et al. (2001) reported in the Journal that variants in the melanocortin-1 receptor modify the risk of melanoma in p16-Leiden carriers. It is interesting that, apart from reports on simultaneous pancreatic tumors, other cancer types have never been found in such families with p16- Leiden (Gruis et al. 1995).Recently, we found a hereditary heterozygous p16-Leiden mutation in a man who neither smoked more than five cigarettes daily nor abused alcohol, initially diagnosed at age 54 years, who simultaneously developed three carcinomas of the pharynx and oral cavity. The patient showed a familial accumulation of tumor diseases. Both of his parents and his only sister died of cancer very early (the mother of gynecologic cancer, the father of liver carcinoma, and the sister of leukemia). Dutch relatives are not known.DNA from tumors and blood was extracted according to a standard protocol (Sambrook et al. 1989). Mutation analysis of exon 1 and exon 2 of the p16 gene was done by PCR-SSCP sequencing as described by Schneider-Stock et al. (1998).The p16-Leiden mutation was found in the heterozygous constitution in all three tumors and in the blood of the patient. We investigated all DNA samples for p16 promotor methylation to check the status of the retained wild-type allele and, thus, to assess the real functional significance of this finding. The methylation status of the p16 promotor was determined by methylation-specific PCR (Herman et al. 1996). The primer sequences for the unmethylated reactions were (sense) 5 -TTA TTA

Extending the p16-Leiden tumour spectrum by respiratory tract tumours

“…In conclusion, the p16-Leiden mutation not only seems to predispose to melanoma and pancreatic tumours but also to head and neck tumours [5][6][7] , and tumours of the lung in some families. Promoter methylation 5 or loss of the wild type allele seems to be the mechanism for the ''second genetic hit''.…”

“…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.…”

Multiple Melanomas After Treatment for Hodgkin Lymphoma in a Non-Dutch p16-Leiden Mutation Carrier With 2 MC1R High-Risk Variants

“…In a more specific instance, in a case of a p16-Leiden mutation carrier with head and neck cancer, the wild-type allele showed promoter methylation in a tumor. 7 The attribution of Hodgkin lymphoma to the CDKN2A mutational status is elusive, although loss of p16 expression in Hodgkin and Reed-Sternberg cells as well as nonHodgkin lymphomas in CDKN2A mutation carriers and leukemia in a first-degree relative of a carrier have been reported. 7,[18][19][20] To date, no report, to our knowledge, has shown Hodgkin lymphoma in CDKN2A Leiden mutation carriers.…”

“…7 The attribution of Hodgkin lymphoma to the CDKN2A mutational status is elusive, although loss of p16 expression in Hodgkin and Reed-Sternberg cells as well as nonHodgkin lymphomas in CDKN2A mutation carriers and leukemia in a first-degree relative of a carrier have been reported. 7,[18][19][20] To date, no report, to our knowledge, has shown Hodgkin lymphoma in CDKN2A Leiden mutation carriers. Furthermore, a strong statistical association has been reported between the occurrence of nonHodgkin lymphoma and cutaneous melanoma.…”

“…Both of his parents and his only sister died of cancer when they were very young (the mother of gynecologic cancer, the father of liver carcinoma, and the sister of leukemia). 7 Other melanoma-prone families with the segregating CDKN2A Leiden mutation have been reported from North America and Australia. 8,9 See also pages 479, 488, 525, and 543…”