Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity

Abstract

Cutaneous T cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled a cohort of CTCLs with representative samples from diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. 2 mutations have never been previously described for any cancer. Functionally, multiple mutations augment T cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways driving diverse disease phenotypes.

PD‐1 improves accurate detection of Sezary cells by flow cytometry in peripheral blood in mycosis fungoides/Sezary syndrome

“…However, even among studies showing overall similar PD‐1 expression levels, some have reported trends toward higher PD‐1 positivity in SS cases (Horna et al, 2019; Khodadoust et al, 2020; Wada et al, 2011). While it has been suggested that this difference in PD‐1 expression may reflect a differing underlying biology of these two entities (Cetinözman et al, 2012), a recent study demonstrated genetic commonalities between MF and SS, suggesting they may represent two extremes of the same disease (Park et al, 2021). This study also showed a correlation between lower‐level PD‐1 protein expression, a proliferative phenotype, and a high frequency of alterations of PDCD1 , the gene that encodes PD‐1, in MF and SS while higher level PD‐1 expression correlated with a non‐proliferative phenotype and a low frequency of PDCD1 alterations.…”

Cutaneous T‐cell lymphomas: 2021 update on diagnosis, risk‐stratification, and management

“…In these cases, the designation "MF with leukemic involvement" is recommended, although genetic features of both MF and SS have been recently described in patients with SS preceded by MF. 15…”

“…The ISCL recommends that such cases be designated as SS preceded by MF or secondary erythrodermic CTCL Conversely, patients with MF, but without erythroderma, may meet hematologic criteria for SS. In these cases, the designation “MF with leukemic involvement” is recommended, although genetic features of both MF and SS have been recently described in patients with SS preceded by MF 15 …”

“…3,9 Patients with CTCL have a higher incidence of secondary malignancies, including other non-Hodgkin lymphomas, lung cancer, bladder cancer, and melanoma, thus meriting appropriate screening. 11,12 While genetic evidence strongly implicates UV radiation as a riskfactor for CTCL, [13][14][15] epidemiological studies have failed to consistently identify other environmental or virally associated risk factors for most CTCL subtypes, with the notable exception of HTLV-1 infection in adult T-cell leukemia/lymphoma. 16 Recent studies, however, have suggested that medications may induce an antigen-driven T-cell lymphoproliferation or dyscrasia.…”

“…While genetic evidence strongly implicates UV radiation as a risk‐factor for CTCL, 13–15 epidemiological studies have failed to consistently identify other environmental or virally associated risk factors for most CTCL subtypes, with the notable exception of HTLV‐1 infection in adult T‐cell leukemia/lymphoma 16 . Recent studies, however, have suggested that medications may induce an antigen‐driven T‐cell lymphoproliferation or dyscrasia 17,18 .…”