Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients With Ovarian Cancer

Abstract

Background: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity.

Methods: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided.

Results: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed.

Conclusions: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.

Figure 1.

Associations between age at blood draw and number of prior platinum-based chemotherapy lines with the occurrence of clonal hematopoiesis (CH)–associated gene mutations. A) Number of CH–associated gene mutations per patient according to the age at blood draw. B) Boxplots for age at blood draw in years stratified by noncarriers (no CH) and carriers (CH) of CH–associated gene mutations and Benjamini-Hochberg-adjusted Welch’s t test P values. Mean lines in boxes correspond to mean values. C) Number of CH–associated gene mutations according to number of prior platinum-based chemotherapy lines. Marker sizes correspond to the number of observed samples. D) Boxplots for numbers of platinum-based chemotherapy lines received stratified by noncarriers (no CH) and carriers (CH) of CH–associated gene mutations and Benjamini-Hochberg-adjusted Welch’s t test P values. Mean lines in boxes correspond to mean values. CI = confidence interval.

Figure 2.

Risk prediction for clonal hematopoiesis (CH)–associated gene mutations based on binomial logistic regression dependent on age at blood draw (age), number of prior platinum-based chemotherapy lines (PtLines), and BRCA1/2 germline mutation status (gBRCA1/2). Coefficients (β), standard errors (SE), odds ratios (OR), 95% confidence intervals (CI), and P values (P, 2-sided Wald test) as obtained from fitting a binomial logistic regression model for the observation of CH–associated gene mutations in ASXL1 (A), DNMT3A (B), TET2 (C), PPM1D (D), and TP53 (E).