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. 2023 Jul 18;24(14):11570.
doi: 10.3390/ijms241411570.

Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer

Edith Borcoman  1   2 , Elizabeth Santana Dos Santos  3 , Catherine Genestie  4   5 , Patricia Pautier  6   7 , Ludovic Lacroix  4 , Sandrine M Caputo  8 , Odile Cabaret  4 , Marine Guillaud-Bataille  4 , Judith Michels  6 , Aurelie Auguste  5 , Alexandra Leary  5   6 , Etienne Rouleau  4   5
Affiliations

Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer

Edith Borcoman et al. Int J Mol Sci. .

Abstract

Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of BRCA1/2-related tumorigenesis.

Keywords: BRCA1/2 tumoral testing; TP53m; allelic frequency; high-grade serous ovarian cancers; loss of heterozygosity; ovarian cancer.

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Conflict of interest statement

E.B. received honoraria from Eisai, Merck Sharp & Dohme, Sandoz, Amgen and meetings/travel grants and non-financial support from Daiichi Sankyo, Eisai, Amgen, Sandoz, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Pfizer, Roche and has consulted for Egle Tx. E.R. declares travel funding by AstraZeneca and board participation for AstraZeneca, BMS, Roche. The remaining authors declare no competing interest.

Figures

Figure 1
Figure 1
Flow chart of tumor-based BRCA1/2 and germline testing.
Figure 2
Figure 2
TP53 tumor samples testing.
See this image and copyright information in PMC

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