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. 2020 Dec 22;13(1):146.
doi: 10.1186/s13048-020-00753-1.

Germline variation of Ribonuclease H2 genes in ovarian cancer patients

Rahel Polaczek  1 , Peter Schürmann  1 , Lisa-Marie Speith  1 , Robert Geffers  2 , Matthias Dürst  3 , Peter Hillemanns  1 , Tjoung-Won Park-Simon  1 , Clemens Liebrich  4 , Thilo Dörk  5
Affiliations

Germline variation of Ribonuclease H2 genes in ovarian cancer patients

Rahel Polaczek et al. J Ovarian Res. .

Abstract

Epithelial ovarian carcinoma (EOC) is a genetically heterogeneous disease that is partly driven by molecular defects in mismatch repair (MMR) or homology-directed DNA repair (HDR). Ribonuclease H2 serves to remove mis-incorporated ribonucleotides from DNA which alleviates HDR mechanisms and guides the MMR machinery. Although Ribonuclease H2 has been implicated in cancer, the role of germline variants for ovarian cancer is unknown. In the present case-control study, we sequenced the coding and flanking untranslated regions of the RNASEH2A, RNASEH2B and RNASEH2C genes, encoding all three subunits of Ribonuclease H2, in a total of 602 German patients with EOC and of 940 healthy females from the same population. We identified one patient with a truncating variant in RNASEH2B, p.C44X, resulting in a premature stop codon. This patient had high-grade serous EOC with an 8 years survival after platinum/taxane-based therapy. Subsequent analysis of TCGA data similarly showed a significantly longer progression-free survival in ovarian cancer patients with low RNASEH2B or RNASEH2C expression levels. In conclusion, loss-of-function variants in Ribonuclease H2 genes are not common predisposing factors in ovarian cancer but the possibility that they modulate therapeutic platinum response deserves further investigation.

Keywords: Epithelial ovarian carcinoma; Homologous recombination; MMR deficiency; Platinum resistance; RNase H2; Ribonucleotide excision repair.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a. Sequencing of RNASEH2B variant p.C44X. Figure legend: Validation of RNASEH2B variant p.C44X through Sanger sequencing in a wildtype control (top) and the index ovarian cancer patient (bottom). The sense strand is shown. Heterozygosity for a T > A transversion was confirmed, changing the cysteine codon TGT to the stop codon TGA. b. Progression-free survival of ovarian cancer patients in relation to RNASEH2B levels. Figure legend: Progression-free survival of ovarian cancer patients in the TCGA database for patients with high versus low RNA levels of RNASEH2B. The Affymetrix probe 229210_at specific for RNASEH2B was used, and patients were stratified using auto-select best cut-off in KMplotter (http://kmplot.com/analysis/index.php?p=service&cancer=ovar) [11]
See this image and copyright information in PMC

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