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Clonal Hematopoiesis Mutation Study Reveals Risk of Treatment-Related Cancer

NEW YORK – A team led by researchers at Memorial Sloan Kettering Cancer Center has uncovered clonal hematopoiesis patterns and genetic mutations that may contribute to the development of new tumors after cancer treatment, known as therapy-related myeloid neoplasms (tMNs).

"We identify the molecular characteristics of [clonal hematopoiesis] that increase risk of tMN," senior authors Elli Papaemmanuiland and Ahmet Zehir, both MSK researchers, and their colleagues wrote, adding that "increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies."

Using variant data generated with the MSK-IMPACT targeted sequencing pipeline on primary tumor samples spanning dozens of cancer types from more than 24,100 patients, the researchers analyzed patient blood samples for clonal hematopoiesis. They uncovered features contributing to tMN but also defined additional ties between prior cancer treatments or other environmental exposures with clonal hematopoiesis. Their findings appeared in Nature Genetics on Monday.

"Mutations in ASXL1 are enriched in current or formers smokers, whereas cancer therapy with radiation, platinum, and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2)," the authors reported.

Moreover, the team saw signs that CH clones that contain alterations affecting DNA damage response genes and pathways may be particularly prone to proliferate in the presence of some therapeutic strategies used to tackle cancer.

"Longitudinal studies of [clonal hematopoiesis] present a unique opportunity to study the patterns of early mutagenesis and the dynamics of clonal selection in the progression towards malignant transformation," the authors explained, noting that the new analysis relied on genetic and epidemiological clues to "provide insights into the mechanisms that drive the transition of a normal [hematopoietic stem and progenitor cell] to a cell with a considerably stronger proliferation advantage, and study how the ensuing trajectories are shaped by host and environmental exposures."

Based on variant allele fraction insights gleaned from targeted sequence profiles for 24,146 cancer cases, the researchers identified almost 11,100 clonal hematopoiesis mutations in blood samples from some 30 percent of the patients profiled, bringing in additional mutation data to dive into exposure-related tumor differences.

The team saw an increase in clonal hematopoiesis in samples from almost 6,000 patients who were previously treated with one of 490 different treatment agents, for example, as they did in samples from individuals with a history of smoking. Clonal hematopoiesis events were more apt to involve suspected driver genes in the cancer therapy and aging contexts, though the specific mutations and clonal patterns differed from one cancer type to the next.

Among the treatment-naïve cases, meanwhile, the researchers uncovered cancer type-related recurrent mutations and clonal hematopoiesis events. While 13 percent of ovarian cancer cases involved PPM1D mutations and 8 percent had PPM1D clonal hematopoiesis events, for example, they did not see such clonal hematopoiesis in the endometrial cancer cases considered, despite the presence of PPM1D mutations in 7 percent of those cancers.

Along with follow-up analyses focused on the effects of specific cancer treatment types, the team took a look at mutation and clonal hematopoiesis patterns in blood samples collected from 525 cancer patients, comparing samples taken over time from individuals receiving chemotherapy or radiation, targeted therapy, immunotherapy, or no treatment. It also got a glimpse at mutations that might predispose individuals to clonal hematopoiesis, including TP53 mutations, and started to untangle the clinical consequences of clonal hematopoiesis.

These and other results from the study "provide a rationale for clinical therapeutical intervention, including the development of therapies aimed to target high-risk [clonal hematopoiesis] clones and modulation of the use of adjuvant systemic cancer therapy in patients at highest risk of subsequent myeloid neoplasm," the authors suggested.

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