Genomic Studies in Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorders Show Alterations That Differ from Aggressive CD30-Positive T-Cell Lymphomas

Background

Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+LPD) such as lymphomatoid papulosis (LYP) and primary cutaneous anaplastic large cell lymphoma (cALCL) tend to have an indolent clinical behavior with localized disease. Patients with systemic ALCL (sALCL) as well as transformed mycosis fungoides (tMF) tend to have a more aggressive clinical course. We sought to determine the genomic differences between these indolent CD30+ cutaneous lesions and how they compare to the more aggressive CD30+ T-cell lymphomas.

Methods

Expert consensus and pathology review in conjunction with in-depth clinical evaluation were performed to identify cases of LYP, cALCL, sALCL, and tMF, according to the 2017 WHO classification. Whole exome sequencing (WES), RNA sequencing on the lesions at presentation were performed. Mutation detection, differential gene expression analysis, and gene set enrichment analysis were performed. The results were also integrated to discover the differences in genomic and epigenomic alterations in these diseases.

Results

We evaluated 38 cases of cALCL, 35 cases of LYP, 7 cases of sALCL (ALK-negative), and 6 cases of tMF. The most frequent mutations in cALCL were FAT4 (21%), HLA-C (18%), ARID1B (18%), and ATM (18%), the most frequent mutations in LYP were KMT2C (26%) and HLA-C (20%). No significant mutational differences were observed between these two indolent diseases. For sALCL, the most frequent mutations were TP53 (38%), KMT2D (25%), and for tMF they were FAT1 (50%), and TP53 (33%). Comparing indolent CD30+LPD (cALCL and LYP) with aggressive T-cell lymphomas (sALCL and tMF), indolent CD30+LPD had fewer TP53 mutations compared to aggressive T-cell lymphomas (11% vs 39%, p=0.02). Interestingly, cutaneous lesions (cALCL, LYP, and tMF) showed alterations related to MHC I (HLA-B, HLA-C) (18%, 34%, 17%, respectively) while sALCL showed no mutations in these genes (0%). Mutations in MHC genes may allow cutaneous tumor cells to evade immune surveillance. In line with the literature, we see frequent mutations related to the FAT genes (FAT1, 2, 3, 4) and the Hippo pathway in cALCL (34%), LYP (34%), sALCL (29%), and tMF (50%), which may reduce stemness and promote cell proliferation and genomic instability. Gene expression analysis of cALCL shows increased expression of MYC targets, cell cycle (E2F), and oxidative phosphorylation relate transcripts, compared to LYP.

Conclusion

In this study, we found that indolent CD30+ lymphoproliferative disorders (cALCL and LYP) have fewer TP53 mutations compared to aggressive T-cell lymphomas (sALCL and tMF). Cutaneous lesions (cALCL, LYP, and tMF) exhibited alterations in MHC genes, which may help tumor cells evade immune surveillance. Additionally, frequent mutations in FAT genes and the Hippo pathway across all subtypes suggest a role in reducing stemness and promoting cell proliferation and genomic instability.

Shinohara:Kyowa Kirin: Consultancy, Research Funding. Querfeld:SIRPant: Other: clinical investigator ; Citius Pharm: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical investigator, Research Funding. Zain:CRISPR Therapeutic: Research Funding; Kyowa Kirin: Speakers Bureau; Dren-Bio: Consultancy, Research Funding; Myeloid: Research Funding; Astex: Research Funding; Secura Bio: Research Funding; Daichi Sankyo: Research Funding; Seattle Genetics: Consultancy. Abdulla:Caris: Current Employment.