Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma.

Abstract

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.

• Authors: Takayuki Sumiyoshi, Toshinari Yamasaki, Masashi Takeda, Kei Mizuno, Noriaki Utsunomiya, Hiromasa Sakamoto, Eijiro Nakamura, Osamu Ogawa, Shusuke Akamatsu
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 8 Pg. 3363-3374 (Aug 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 34009695 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Biomarkers, Tumor
• Cell-Free Nucleic Acids
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics)
• Carcinoma, Renal Cell (genetics)
• Case-Control Studies
• Cell Line, Tumor
• Cell-Free Nucleic Acids (genetics)
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Sequence Analysis, DNA
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)