Profiling of Copy Number Alterations Using Low-Coverage Whole-Genome Sequencing Informs Differential Diagnosis and Prognosis in Primary Cutaneous Follicle Center Lymphoma

Bence Bátai; Laura Kiss; Luca Varga; Ákos Nagy; Jacob Househam; Ann-Marie Baker; Tamás László; Anna Udvari; Róbert Horváth; Tibor Nagy; Judit Csomor; József Szakonyi; Tamás Schneider; Trevor A Graham; Donát Alpár; Jude Fitzgibbon; Ágota Szepesi; Csaba Bödör

doi:10.1016/j.modpat.2024.100465

Profiling of Copy Number Alterations Using Low-Coverage Whole-Genome Sequencing Informs Differential Diagnosis and Prognosis in Primary Cutaneous Follicle Center Lymphoma

Mod Pathol. 2024 Mar 7;37(5):100465. doi: 10.1016/j.modpat.2024.100465. Online ahead of print.

Authors

Bence Bátai¹, Laura Kiss², Luca Varga², Ákos Nagy¹, Jacob Househam³, Ann-Marie Baker³, Tamás László², Anna Udvari², Róbert Horváth², Tibor Nagy⁴, Judit Csomor⁵, József Szakonyi⁶, Tamás Schneider⁷, Trevor A Graham³, Donát Alpár², Jude Fitzgibbon⁸, Ágota Szepesi⁹, Csaba Bödör¹⁰

Affiliations

¹ HCEMM-SU Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary.
² HCEMM-SU Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
³ Genomics and Evolutionary Dynamics Team, Centre for Evolution and Cancer, The Institute for Cancer Research, London, UK.
⁴ HCEMM-SU Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁵ Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
⁶ Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary.
⁷ Department of Hematology and Lymphoma, National Institute of Oncology, Budapest, Hungary.
⁸ Barts Cancer Institute, Queen Mary University of London, London, UK.
⁹ Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. Electronic address: szepesi.agota@semmelweis.hu.
¹⁰ HCEMM-SU Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. Electronic address: bodor.csaba1@semmelweis.hu.

PMID: 38460675
DOI: 10.1016/j.modpat.2024.100465

Abstract

Primary cutaneous follicle center lymphoma (PCFCL) has an excellent prognosis using local treatment, whereas nodal follicular lymphoma (nFL), occasionally presenting with cutaneous spread, often requires systemic therapy. Distinction of the 2 diseases based on histopathology alone might be challenging. Copy number alterations (CNAs) have scarcely been explored on a genome-wide scale in PCFCL; however, they might serve as potential biomarkers during differential diagnosis and risk stratification. Low-coverage whole-genome sequencing is a robust, high-throughput method for genome-wide copy number profiling. In this study, we analyzed 28 PCFCL samples from 20 patients and compared the copy number profiles with a cohort of diagnostic samples of 64 nFL patients. Although the copy number profile of PCFCL was similar to that of nFL, PCFCL lacked amplifications of 18q, with the frequency peaking at 18q21.33 in nFL cases involving the BCL2 locus (PCFCL: 5.0% vs nFL: 31.3%, P = .018, Fisher exact test). Development of distant cutaneous spread was significantly associated with higher genomic instability including the proportion of genome altered (0.02 vs 0.13, P = .033) and number of CNAs (2 vs 9 P = .017), as well as the enrichment of 2p22.2-p15 amplification involving REL and XPO1 (6.3% vs 60.0%, P = .005), 3q23-q24 amplification (0.0% vs 50.0%, P = .004), 6q16.1-q23.3 deletion (6.3% vs 50.0%, P = .018), and 9p21.3 deletion covering CDKN2A and CDKN2B loci (0.0% vs 40.0%, P = .014, all Fisher exact test) in PCFCL. Analysis of sequential tumor samples in 2 cases harboring an unfavorable clinical course pointed to the acquisition of 2p amplification in the earliest common progenitor underlining its pivotal role in malignant transformation. By performing genome-wide copy number profiling on the largest patient cohort to date, we identified distinctive CNA alterations conceivably facilitating the differential diagnosis of PCFCL and secondary cutaneous involvement of nFL and potentially aiding the risk stratification of patients with PCFCL in the future.

Keywords: copy number profiling; cutaneous lymphoma; genomics; next-generation sequencing.