Sequencing‐based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy

Abstract

Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole‐exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.

Prognostic value of CDKN2A in head and neck squamous cell carcinoma via pathomics and machine learning

“…Building upon the foundational work in the field, our findings echo and extend the narrative around CDKN2A's prognostic significance in cancer. 24 , 25 , 26 For instance, Swati et al. 's 27 investigation into the relationship between CDKN2A/p16 expression and recurrence in Indian oral squamous cell carcinoma aligns with our insights, underlining the gene's broader applicability as a biomarker.…”

Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma

“… 5 , 32 , 50 Recent WGS, whole-exome sequencing (WES), and targeted approaches allowed the identification of new alterations in cell cycle genes ( SAMHD1, CDKN1B ), and alterations in new pathways such as telomere maintenance ( TERT ), chromatin remodelers ( KMT2D/C, NSD2, SMARCA4, and SP140 ), NF-κB signaling pathways ( BIRC3, CARD11, TRAF2, and TLR2 ), NOTCH pathway ( NOTCH1/2 ), and other genes ( HNRNPH1 and UBR5 ). 5 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 In 42 blastoid MCL analyzed by WES, mutations of NOTCH2 , NOTCH3 , and UBR5 were exclusively found, whereas NOTCH1 mutations were enriched in blastoid compared with nonblastoid forms. 33 …”

“… The number of cases used for single nucleotide variant and insertions and deletions (mutations) analyses is 432, based on references Karolová et al 35 ; Yi et al 32 ; Nadeu et al 5 ; Pararjalingam et al 36 ; Jeong et al 37 ; Jain et al 33 ; Agarwal et al 38 ; Yang et al 39 ; Wu et al 40 ; Zhang et al 41 ; Khodadoust et al. 42 The number of cases used for CNA is 202, based on references Yi et al 32 and Nadeu et al.…”

“…We performed a systematic review of 11 recent WGS and WES studies of MCL 5 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 at diagnosis, including 432 cases, considering only single nucleotide variants and insertions and deletions. The most frequently altered (>13%) genes were ATM , TP53 , CCND1 , KMT2D , and NSD2 ( Figure 2 C; Table 1 ).…”

“…In 2 WES studies with 11 32 and 25 35 patients with MCL samples before and after standard chemoimmunotherapy, the authors noted a very high frequency of acquired CDKN2A deletions, TP53 mutations/deletions, and less frequently other high-risk genetic alterations, such as KMT2D, NOTCH1, NOTCH2, SMARCA4 , and SP140. The resistant MCL clones detected at relapse were already present at diagnosis and were selected for therapy.…”