Certain Low-Prevalence Mutations May Be Strong Drivers in Pediatric ALL

The most common mutations in certain leukemias may not always be the strongest drivers of cancer effects, study findings suggest.¹

The findings, published in International Journal of Molecular Science, revealed that despite not being highly prevalent across the patient population, certain moderately or infrequently occurring mutations in acute lymphoblastic leukemia (ALL) may have some of largest cancer effects in young patients with T-cell and B-cell disease.

Most genomic analyses have traditionally focused on commonly mutated genes, which can pinpoint mutations occurring most frequently but does not account for the extent to which these mutations impact cancer cell survival and proliferation. | Image Credit: © lucadp - stock.adobe.com

The researchers noted that most genomic analyses have traditionally focused on commonly mutated genes, which can pinpoint mutations occurring most frequently but does not account for the extent to which these mutations impact cancer cell survival and proliferation. From their analysis, the researchers identified 3 less commonly mutated genes in T-cell disease and another 3 in B-cell disease, offering insight into potential new treatment targets.

“By estimating cancer effects for somatic mutations, we have elucidated their differential genetic landscape, and the extent to which specific mutations contribute to cancer phenotypes, crucial information that provides valuable insights into potential therapeutic targets,” detailed the researchers in their analysis. “Mutations in genes such as PIK3R1, RPL10, and NRAS exhibit substantial cancer effects in T-cell ALL, and are present at low prevalence. However, when present, they appear to be pivotal drivers for malignant transformation and cell survival.”

The group analyzed data from the largest publicly available T-ALL and B-ALL sequencing dataset. The cohort includes 2700 pediatric patients with ALL, analysis of which has previously indicated that despite a lower mutation burden, all patients harbored a median of 4 putative somatic driver alterations per sample.²

In this new analysis, researchers measured the effects of each gene by estimating a shared scale selection coefficient across mutation sited of each gene that had more than 4 substitutions.¹ While single-nucleotide mutations in PIK3R1, a protein coding gene, were among those commonly observed, this kind of mutation was observed at a markedly lower prevalence than other mutations in genes such as KRAS and NOTCH1.

Despite a lower prevalence, PIK3R1 showed the strongest effect on cancer. PIK3R1 is a subunit of PI3K, other subunits of which have been known to drive various cancer types. Research has explored targeting PI3K, sometimes dubbed as the “master regulator for cancer,” to inhibit tumor progression.³ Several PI3K inhibitors have been greenlit by the FDA, though their use has been stifled by safety concerns.^4,5

RPL10 and NRAS—common in other cancers but uncommonly seen in ALL—were also identified as having significant cancer effects despite their low prevalence in T-cell disease.¹ The researchers highlighted RPL10 as a particularly unusual driver in T-cell disease, promoting JAK-STAT oncogenic signaling, increasing oxidative stress and proliferations, promoting mutagenesis, and acquiring rescuing mutations that promote proliferation.

In B-cell disease, the researchers found low prevalence of mutations in IL7R, XBP1, and TOX, all of which were among the strongest drivers in cancer effects. IL7R has been shown to play a key role in B-cell ALL, among other leukemias. XBP1 is a key regulator of oncogenic unfolded protein response, and TOX has previously shown effects in regulating growth, DNA repair, and genomic instability in T-cell disease.

“Other mutations at low prevalence and even low effect may also be crucially important in a distinct co-occurring genetic context or molecularly defined subtype; for instance, the single-nucleotide mutations of CDKN2A in B-cell and T-cell ALL have a low estimate of effect ignoring context, but the high frequency of CDKN2A deletions and their co-occurrence with substitutions (3 out of 5 T-ALL patients with CDKN2A substitutions have the focal deletion of the other copy; among B-ALL patients, 4 out of 12) indicate a large selective epistatic effect,” explained the researchers.

“Prioritizing the investigation of these high-impact targets not only opens new avenues for potentially highly effective therapeutic targets but also provides valuable insights into the intricate mechanisms driving the disease, thereby advancing our understanding and ultimately leading to improvements in precision therapeutics.”

References

1. Mandel JD, Diviti S, Xu M, Townsend JP. Rare drivers at low prevalence with high cancer effects in T-cell and B-cell pediatric acute lymphoblastic leukemia. Int J Mol Sci. 2024;25(12):6589. doi:10.3390/ijms25126589
2. Brady SW, Roberts KG, Gu Z, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet. 2022;54(9):1376-1389. doi:10.1038/s41588-022-01159-z
3. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019;18(26). doi:10.1186/s12943-019-0954-x
4. Lawrence L. PI3K inhibitors: a series of unfortunate events. ASH Clinical News. January 2024. Accessed July 3, 2024. https://ashpublications.org/ashclinicalnews/news/7684/PI3K-Inhibitors-A-Series-of-Unfortunate-Events
5. Yu M, Chen J, Xu Z, et al. Development and safety of PI3K inhibitors in cancer. Arch Toxicol. 2023;97(3):635-650. doi:10.1007/s00204-023-03440-4