A mutation at IVS1 + 5 of the von Hippel-Lindau gene resulting in intron retention in transcripts is not pathogenic in a patient with a tongue cancer?: case report

We describe a case of squamous cell carcinoma in the tongue caused by a point mutation in the splicing region of the VHL gene and discuss its association with VHL disease. Sequence analysis of DNA extracted from the tumor and peripheral blood of the patient with squamous cell carcinoma revealed a heterozygous germline mutation (c. 340 + 5 G > C) in the splice donor sequence in intron 1 of the VHL gene. RT-PCR analysis of the exon1/intron1 junction in RNA from tumor tissue detected an unspliced transcript. Analysis of LOH using a marker with a heterozygous mutation of nucleotides (G or C) revealed a deletion of the mutant C allele in the carcinoma tissues.The fifth nucleotide G of the splice donor site of the VHL gene is important for the efficiency of splicing at that site. The development of tongue cancer in this patient was not associated with VHL disease because the mutation occurred in only a single allele of the VHL gene and that allele was deleted in tumor cells.Von Hippel-Lindau (VHL) disease has a prevalence of about 1 per 36,000 people with 20% of cases being sporadic and 80% familial [1,2]. The causal gene, VHL, is located on chromosome 3p26-25 and is known to act as a tumor-suppressor gene [3]. It has three exons that code for 213 amino acids and has functions to promote ubiquitination of hypoxia inducible factor 1- alpha [4]. There are characteristic abnormalities of the VHL gene in germline mutations from VHL disease and somatic mutations from sporadic cancers: more than a half of the former are missense mutations whereas 70% of the latter are frameshift mutations [5,6]. Thus, most pathogenic mutations are located in the coding region of the VHL gene. There are a few cases with splicing abnormality of the VHL gene and it is not yet clear whether an abnormal transcript of the VHL is pathogenic. In this report, we describe a splicing abnormality of the VHL gene in a patient with a squamous cell carcinoma (SCC) of the tongue.The patient is a 55-year male w