Large-Scale Genomic Analysis Gives New Insights Into the Chronology, Evolution of CLL

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Researchers have identified 55 genetic driver events involved in the development and progression of CLL.
Researchers have identified 55 genetic driver events involved in the development and progression of CLL.

Using whole-exome sequencing (WES) from a large sample of chronic lymphocytic leukemia (CLL) cells, researchers have identified 55 genetic driver events involved in the development and progression of the disease, including 2 not previously known to be involved in human cancer development.1

The study, published in a recent issue of Nature, was conducted under the auspices of Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard by senior author Catherine J. Wu, MD, and colleagues.

Data from 538 tumor cell and matched somatic cell samples were analyzed, including 278 samples from a single randomized trial of chemotherapy versus chemoimmunotherapy, the CLL8 study.

With the advantage of a large number of samples, the researchers were able to detect genetic changes that are present in relatively small numbers of patients (5%), and with reasonably high power to detect genes mutated in as few as 2% of patients (61% power).

“Previous studies were limited by the relatively small number of tumor tissue samples analyzed and by the fact that those samples were taken at different stages of the treatment process from patients treated with different drug agents,” Dr. Wu told Cancer Therapy Advisor.

The analysis identified 44 non-silent single-nucleotide variants (sSNVs) and somatic insertions and deletions (sIndel), and 11 somatic copy number alterations (CNAs). The size of the cohort also allowed researchers to examine associations between key features of CLL and genetic changes.

The results yielded insights into several key areas of CLL, including the relationship between genetic drivers and disease characteristics and between specific genetic mutations and clinical outcome, the temporal evolution of genetic changes, and clonal evolution at relapse.

The 2 mutated genes not previously associated with human cancer are RPS15 and IKZF3. The clinical impact of RPS15 is its association with shorter progression-free survival, a clinical outcome also associated with TP53 and SF3B1 mutations. IKZF3 is enriched in samples from relapsed disease and may confer a fitness advantage that allows tumor cells to proliferate under therapeutic pressure.

The researchers also were able to explore the sequence in which driver genes occurred or were acquired in the evolution of CLL, creating a temporal map of the disease. It appeared that somatic CNAs were the earliest events, with distinct starting points at del(13q) and tri(12) followed by early convergence toward del(11q).

Their role as early events in disease was confirmed by the finding that these 3 generally remain stable throughout clonal evolution and relapse.

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Another finding was that loss-of-copy mutations in tumor suppressor genes ATM and BIRC3 appeared to precede certain mutations in tumors with biallelic inactivation. Driver events also occurred in pairs, the most predominant being TP53 and del(17p).

Large clonal shifts were found between pretreatment samples and relapse samples, indicating that CLL evolution after therapy is “the rule rather than the exception,” according to Dr. Wu.

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