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Menzel, M.* ; Endris, V.* ; Schwab, C.* ; Kluck, K.* ; Neumann, O.* ; Beck, S.* ; Ball, M.* ; Schaaf, C.* ; Fröhling, S.* ; Lichtner, P. ; Schirmacher, P.* ; Kazdal, D.* ; Stenzinger, A.* ; Budczies, J.*

Accurate tumor purity determination is critical for the analysis of homologous recombination deficiency (HRD).

Transl. Oncol. 35:101706 (2023)
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Homologous recombination deficiency (HRD) is a predictive marker for response to poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian carcinoma. HRD scores have entered routine diagnostics, but the influence of algorithms, parameters and confounders has not been analyzed comprehensively. A series of 100 poorly differentiated ovarian carcinoma samples was analyzed using whole exome sequencing (WES) and genotyping. Tumor purity was determined using conventional pathology, digital pathology, and two bioinformatic methods. HRD scores were calculated from copy number profiles determined by Sequenza and by Sclust either with or without fixed tumor purity. Tumor purity determination by digital pathology combined with a tumory purity informed variant of Sequenza served as reference method for HRD scoring. Seven tumors had deleterious mutations in BRCA1/2, 12 tumors had deleterious mutations in other homologous recombination repair (HRR) genes, 18 tumors had variants of unknown significance (VUS) in BRCA1/2 or other HRR genes, while the remaining 63 tumors had no relevant alterations. Using the reference method for HRD scoring, 68 tumors were HRD-positive. HRDsum determined by WES correlated strongly with HRDsum determined by single nucleotide polymorphism (SNP) arrays (R = 0.85). Conventional pathology systematically overestimated tumor purity by 8% compared to digital pathology. All investigated methods agreed on classifying the deleterious BRCA1/2-mutated tumors as HRD-positive, but discrepancies were observed for some of the remaining tumors. Discordant HRD classification of 11% of the tumors was observed comparing the tumor purity uninformed default of Sequenza and the reference method. In conclusion, tumor purity is a critical factor for the determination of HRD scores. Assistance by digital pathology helps to improve accuracy and imprecision of its estimation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Homologous Recombination Deficiency ; Hrd ; Tumor Cell Content ; Tumor Purity ; Wes ; Whole Exome Sequencing; Copy-number Analysis; Dna-repair; Defects
Language english
Publication Year 2023
HGF-reported in Year 2023
e-ISSN 1936-5233
Journal Translational Oncology
Quellenangaben Volume: 35, Issue: , Pages: , Article Number: 101706 Supplement: ,
Publisher Neoplasia Press
Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa
Reviewing status Peer reviewed
Institute(s) CF Genomics (CF-GEN)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
PSP Element(s) A-632700-001
DOI 10.1016/j.tranon.2023.101706
WOS ID 001024657100001
Scopus ID 85162151243
PubMed ID 37327584
Erfassungsdatum 2023-10-18
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