AB175. The first large-scale study of VHL gene mutation spectrum and genotype-phenotype correlationship of VHL disease in China

Objective: VHL disease is the most common hereditary renal cancer, and it is an autosomal-dominant inherited familial cancer syndrome caused by germline mutations of the VHL tumor suppressor gene. The golden standard for diagnosing VHL disease is to find the VHL gene mutation in patients’ genes. In the world, the United States had summarized 469 VHL families from the United States, Europe and Japan to summarize VHL gene mutation spectrum and the genotype-phenotype correlationship. However, no such large number of samples’ analysis had been done in China. The purpose of this study is to finish the first large-scale study of VHL gene mutation spectrum and genotype-phenotype correlationship of VHL disease in China.

Methods: We have gathered 172 Chinese VHL families including 89 families diagnosed in our hospital and 83 families from other domestic hospitals gathered by literature summary. Then we made statistical analysis of data from 172 Chinese VHL families.

Results: In the 172 Chinese VHL families, germline mutations were identified in 165 (96%) families. Point mutations were found in 103 (62%) families, large deletions were found in 32 (19%) families, micro-deletions or micro-insertions were found in 21 (13%) families, and splice mutations were found in 9 (6%) families. We found 9 hot mutation codons that affected more than 4 families each, and they were codon65, codon76, codon78, codon80, codon86, codon88, codon161, codon162 and codon167. The onset of pheochromocytoma in VHL patients was related to mutations in VHL gene locus 482, 482, 499, 499. Mutations in VHL gene locus 257, 257, 481 was negatively related to the onset of pheochromocytoma. The occurrence of retinal angioma associated with VHL gene large deletions. Mutations in VHL gene locus 226, 233, 239, 257, 263, 481, 486, 499, 500 was related to the onset of renal cell carcinoma.

Conclusions: We have finished the first large-scale study of VHL gene mutation spectrum and genotype-phenotype correlationship of VHL disease in China. Summarizing VHL gene mutation spectrum can help to find the clinical characteristic of VHL disease and help the pathogenesis research. Genotype-phenotype correlation research can help predicting onset and evaluating prognosis of the patients.

Keywords: VHL disease; renal cell carcinoma; genotype; phenotype