Chemotherapy-induced mutations in genes of clonal hematopoiesis increase the risk of myeloid neoplasms

Objective To identify acquired blood-specific mutations in clonal hematopoiesis (CH) genes that influence the risk of secondary, therapy-associated myeloid neoplasia.

Materials and Methods Retrospective analysis of 448 patients with ovarian cancer (OC) enrolled in AGO-TR1-a retrospective cohort trial to evaluate the frequency of BRCA mutations in patients with OC. The following CH-associated genes were analyzed with NGS in germline DNA derived from blood cells. ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53 were analysed with. Results were correlated with BRCA 1/2 status.

Results Older age and number of prior platinum-based chemotherapy lines were risk factors associated with increased frequency of acquired CH-associated mutations. Logistic regression analyses in gBRCA1/2 mutation carriers showed increased probabilities of acquired KH-associated mutations in PPM1D and TP53 (PPM1D: odds ratio (OR): 4.30, 95% CI:1.48 -12.46, P=.007; TP53: OR: 6.20, 95% CI:0.98- 53.9, P=.06). This observation was based on an increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs nonmutation carriers (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). There was no interaction between platinum-containing chemotherapy and gBRCA1/2 mutation status.

Summary gBRCA1/2 mutations are not risk factors for CH-associated gene mutations. Patients with OC may benefit from monitoring KH-associated genes after platinum-containing chemotherapy. Future studies should evaluate how far treatment regimens should be adjusted for the risk of developing therapy-associated myeloid neoplasms.

Publikationsverlauf

Artikel online veröffentlicht:
11. Oktober 2022