Co-Occurrence of del(6q), RPS15 May Drive Poor Prognosis in CLL

Patients with chronic lymphocytic leukemia (CLL) who have chromosome 6q deletion (del[6q]) may have a frequency of certain mutations that yield poor outcomes, suggest researchers.¹

In a letter to the editor published in the American Journal of Hematology, researchers outlined their findings of a small sample set of patients with del(6q), a less frequent cytogenetic alteration found in patients with CLL. In addition to occurring as a secondary abnormality, del(6q) may also occur as the first and only cytogenetic alteration, they found.

Across del(6q) samples, the mutational landscape varied based on whether other cytogenetic alterations were present. | Image Credit: © momius - stock.adobe.com

“Several studies have suggested an association of del(6q) with inferior outcomes, allocating these CLL cases in an intermediate-risk category, although other studies have shown no difference in outcomes,” explained the researchers. “The recurrence of del(6q) in other B-cell malignancies strongly suggests that this region contains unidentified tumor-suppressor gene(s). Nevertheless, CLL patients harboring del(6q) remain poorly characterized at the molecular level, partly due to the low incidence of cases, the lack of a FISH-based routinely assessment of del(6q), and the co-occurrence with other abnormalities that masks their clinical and biological significance.”

The group analyzed data from 38 patient samples with del(6q) from 4 hospitals—2 in the US, 1 in Italy, and 1 in Spain. In 15 samples, del(6q) was the sole abnormality identified, whereas 23 samples showed del(6q) as the one of multiple cytogenic alterations.

In their data set, time to first treatment (TTFT) for patients with del(6q) as the sole genetic abnormality was significantly shorter than that for a cohort of 317 controls but was similar to that of patients with additional cytogenetic abnormalities.

This finding, said the researchers, supports previous findings that worse prognosis, including shorter treatment-free survival, in patients with del(6q) is not solely a result of genomic instability or presence of multiple genetic alterations.^2,3

Compared with the cohort of controls, who were representative of CLL characteristics, patients with del(6q) had several adverse factors, including being younger at diagnosis (median age, 61 years vs 72 years; P < .001) and having unmutated IGHV (75% vs 45.7%; P = .005).

Across del(6q) samples, the mutational landscape varied based on whether other cytogenetic alterations were present.

“Surprisingly, the most frequently mutated gene in del(6q)-only CLL patients was RPS15 (40%). RPS15 gene encodes for the ribosomal subunit S15, located in the short arm of chromosome 19. In treatment naïve CLL patients, RPS15 mutations are infrequent (~4%), but enriched at relapse or in high-risk subgroups such as del17p (~20%),” explained the researchers, noting that “Within the whole del(6q) cohort (N = 38),TTFT of patients harboring RPS15 mutations was shorter than the rest of del(6q) cases without this gene mutated and shorter than patients harboring RPS15 mutations in the control group, demonstrating the prognostic significance of the co-occurrence of del(6q) and RPS15 mutations.”

In these patients, XPO1 and ATM also occurred at a higher frequency, each present in 20% of samples.

Among the 23 samples with del(6q) and other cytogenetic alterations, TP53 (35%), NOTCH1 (17%), and NFKBIE (17%) occurred most frequently.

References:

1. Carretero CP, González T, Álamo MQ, et al. Chronic lymphocytic leukemia patients with chromosome 6q deletion as the sole cytogenetic abnormality display a high frequency of RPS15 mutations and have a poor prognosis. Am J Hematol. Published online July 1, 2024. doi:10.1002/ajh.27421

2. Audil HY, Hampel PJ, Van Dye DL, et al. The prognostic significance of del6q23 in chronic lymphocytic leukemia. Am J Hematol. 2021;96(6):e203-e206. doi:10.1002/ajh.26168

3. Wang D-M, Miao K-R, Fan L, et al. Intermediate prognosis of 6q deletion in chronic lymphocytic leukemia. Leuk Lymphoma. 2011;52(2):230-237. doi:10.3109/10428194.2010.542599