Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma

Abstract

The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.

RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma

“…31 Subsequently, clonal heterogeneity in ATL based on mutation profiles of cross-sectional, whole-exome sequencing samples has been monitored, and subclonal admixtures containing specific mutations have been proposed. 32 In the current study, we focused on developing an understanding of clonal architecture based on TCR profiles in ATL. To our knowledge, this is the first report of TCR clonal architecture in ATL using RNA-seq.…”

Precision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed

“…The impact of ITH on drug resistance and targeted therapy strategies has been demonstrated using multiple-site profiling in solid tumors and is regarded as a paradigm shift in cancer care [ 42 ]. In contrast, only a limited number of studies addressed ITH in non-solid tumors [ 43 , 44 , 45 , 46 ]. Wogsland et al studied intra- and inter-tumor heterogeneity of follicular lymphoma (FL), a B-cell malignancy, by using mass cytometry to obtain deep profiling of cell subsets [ 43 ].…”

“…The diagnosis of primary and metastatic tumors is typically based on a single biopsy representing only a snapshot of ongoing tumor evolution and may be compromised by ITH [ 49 ]. The studies described above show that a sole biopsy does not accurately capture the tumor’s genetic and phenotypic heterogeneity [ 28 , 46 ]. Therefore, multimodal strategies have to be taken into account to ensure patients receive effective and targeted therapy.…”

Biomarkers and Preclinical Models for Adult T-Cell Leukemia-Lymphoma Treatment

“…This was first identified by Southern blot analysis of HTLV-1 provirus integration, and more recently by next-generation sequencing methods of integration sites (Yamaguchi et al, 1984; Gillet et al, 2011). Alternatively, variant allele frequency measurements of specific ATL genetic abnormalities provide an alternative measurement of clonal outgrowth of ATL (Farmanbar et al, 2018). Laydon et al (2014) and Farmanbar et al (2019) also reported quantification of HTLV-1 clonality using TCR diversity analysis.…”

“…However, we have identified subjects in whom two or more TCR gene rearrangements are present within a population of ATL cells with a single proviral integration site (Rauch et al, 2019). Moreover, intratumor heterogeneity has been shown to be a complex and early event in the development of ATL (Farmanbar et al, 2018).…”