Meta-Analysis Highlights Commonly Mutated Genes in Mantle Cell Lymphoma

The frequency of mutations in patients with mantle cell lymphoma (MCL) has a tendency to increase at clinical turning points like disease relapse and progression compared with at the time of diagnosis, according to a systemic review and meta-analysis published in Blood Advances.¹

A team of authors from the MD Anderson Cancer Center, Mayo Clinic, and Pennsylvania State College of Medicine conducted this analysis to examine the prevalence of genetic mutations in patients with MCL, determine methods of sequencing and genotyping, and demonstrate the possible clinical significance of these mutations.

The authors, led by Michael L. Wang, MD, of MD Anderson, reviewed the genetics of 2275 MCL tumor or bone marrow samples taken at baseline and observed that nearly half (43.5%) contained mutated ATM. The next most frequently mutated gene was TP53 (26.8%), followed by CDKN2A (23.9%) and CCND1 (20.2%). Cytogenetic methods also detected aberrations in IGH (38.4%) and MYC (20.8%). Additional common baseline mutations included NSD2 (15.0%), KMT2A (8.9%), S1PR1 (8.6%), and CARD11 (8.5%).

The study authors also identified the genes with the highest mutational frequency difference (>5%). These include TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A, and S1PR1.

Based on the pooled analysis, the study authors focused on 32 genes, out of 164, that were found to be frequently mutated in at least one of the studies. Wang et al found the overall probability of having a genetic mutation in these 32 genes to be 11.3% at baseline (95% CI, 9.3%-13.4%). For patients tested again after relapse or progression, the probability of having a mutation in one of these genes had increased to 18.4% (95% CI, 14.9%-22.4%). “The oncogenic role of these aberrations as driver mutations in clonal evolution and expansion should be further studied,” they wrote. “Targeted panels for MCL could be constructed using genes with the highest mutational rate combined with recurrently mutated regions of the genes to understand their clinical relevance in the era of novel precision therapies.”

At disease progression, the most common genetic mutations were ATM (57.6%), TP53 (43.0%), CDKN2A (29.5%), and CCND1 (27.7%).

The biggest difference from baseline to disease progression was seen in the TP53 gene, where the frequency was 26.8% at baseline up to 43.0% at disease progression (Bayesian probability, 0.998).

The authors performed a literature search of 3 major databases for original studies that reported genetic mutations in patients with MCL, including randomized clinical trials, prospective studies, retrospective studies, and case reports. They excluded studies that reported only conventional cytogenetics such as gains, deletions, and translocations, as well as gene expression data without genetic mutation data.

Extracted data included mutational data (whether a gene was mutated), type of study (observational or experimental), the technology used to analyze mutations, sample collection time point (baseline/diagnosis, relapse, progression), and if a specific treatment or therapy was named in the study. They collected both study-level and patient-level data. After initially identifying 1577 unique studies, Wang et al culled studies that didn’t meet the inclusion criteria until they were left with 32 to include in the final analysis.

The 32 included studies included 2275 samples from 2127 patients. Overall, 2045 of 2127 patients with MCL had baseline samples with genetic mutation information for at least 1 of the 32 genes. Studies from the pre-genomic era generally used techniques such as Sanger sequencing, probed fluorescence in situ hybridization, and polymerase chain reaction to identify mutations. More recent studies have frequently used single-nucleotide polymorphism arrays and next-generation sequencing (NGS).

Wang et al urged the inclusion of all genes with >5% increase in mutational frequency in future genomic and functional studies “to understand their role in the relapse and progression of MCL and be included in targeted NGS panels,” they wrote. “The patient-level data of prevalent mutations in MCL provide additional evidence to existing literature highlighting the importance of molecular variability in advancing precision medicine initiatives in MCL.”

In assessing their paper’s strength and weaknesses, Wang et al emphasized their inclusion of patient-level data as increasing the quality and reliability of their data. Despite their efforts, they note that their study is subject to the small-study effect due to the rarity of MCL and the relatively low number of genetic studies done to date. Additionally, MCL tissue banks are used for many genotyping/sequencing studies, so it’s possible that some patient samples have been used in multiple studies. “However, we believe that each patient observed in the 32 studies was genotyped/sequenced uniquely for that particular study and represents an independent observation,” they wrote.

The authors also noted that additional articles reporting mutations in patients with MCL were published after their study period: “These articles describe prevalent mutations similar to those reported in our analysis, including ATM, TP53, NOTCH1, and CCND1.” ^2-6

_References:

_{1. Hill HA, Qi X, Jain P, et al. Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis. Blood Adv. 2020;4(13):2927-2938. doi:10.1182/bloodadvances.2019001350.}

_{2. Jain P, Zhang S, Kanagal-Shamanna R, et al. Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL. Blood Adv. 2020;4(6):1038-1050. doi:10.1182/bloodadvances.2019001396}

_{3. Streich L, Sukhanova M, Lu X, et al. Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: a multi-institutional study. Genes Chromosomes Cancer. 2020;59(8):484-494. doi:10.1002/gcc.22849}

_{4. Swenson S, Gilbreath T, Vahle HE, et al. UBR5 HECT domain mutations in mantle cell lymphoma control maturation of B cells Blood. 2020;136(3):299-312. doi:10.1182/blood.2019002102}

_{5. Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. Am J Hematol. 2020;95(6):623-629. doi:10.1002/ajh.25796}

_{6. Pararajalingam P, Coyle KM, Arthur S, et al. Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing. Blood. 2020;136(5):572-584. doi:10.1182/blood.2019002385}