Genomics of Classical Hodgkin Lymphoma

Multiple genomic alterations contribute to immune evasion in Hodgkin lymphoma.

Multiple genomic alterations contribute to immune evasion in Hodgkin lymphoma.

Copy number gain or amplification at chromosome 9p24 is observed in most cases of Hodgkin lymphoma.[8,9] This region encodes the immune checkpoint genes CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2). These genomic alterations lead to increased expression of these checkpoint proteins.[8,9]

Multiple genomic alterations contribute to immune evasion in Hodgkin lymphoma.

Gene fusions involving CIITA, which is the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, were reported in 15% of Hodgkin lymphoma cases.[10] Similar alterations are found in primary mediastinal B-cell lymphoma, and they lead to decreased CIITA protein expression and loss of MHC class II expression.[10,11]

Multiple genomic alterations contribute to immune evasion in Hodgkin lymphoma.

Beta-2-microglobulin (the invariant chain of the MHC class I) frequently shows decreased/absent expression in HRS cells, with accompanying decreased MHC class I expression.[12] Inactivating variants in B2M, the gene that encodes beta-2-microglobulin, are common in Hodgkin lymphoma and lead to reduced expression of MHC class I.[2,4] Inactivating variants in B2M occur more frequently in Epstein-Barr virus (EBV)-negative Hodgkin lymphoma than in EBV-positive Hodgkin lymphoma,[2] which explains the higher rates of beta-2 microglobulin and MHC class I expression for EBV-positive Hodgkin lymphoma, compared with EBV-negative Hodgkin lymphoma.[12]

Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

SOCS1, a negative regulator of JAK-STAT signaling, is inactivated by variants in 60% to 70% of Hodgkin lymphoma cases.[3] In a study of pediatric Hodgkin lymphoma using cfDNA collected before treatment, SOCS1 was the most frequently altered gene, with variants in 60% of all cases and approximately 80% of cases in which genomic alterations were detected in cfDNA.[13]

Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

Activating STAT6 variants occurring at hot spots in the DNA-binding domain are observed in approximately 30% of Hodgkin lymphoma cases.[2,3]

Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

The chromosome 9p region that contains CD274 and PDCD1LG2, which shows gains and amplifications in Hodgkin lymphoma, also contains JAK2.[2,3,14] Chromosome 9p gain/amplification is thought to further augment JAK-STAT pathway signaling.[14]

Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

Inactivating variants in PTPN1, a phosphatase that inhibits JAK-STAT pathway signaling, were observed in approximately 20% of Hodgkin lymphoma cases.[2,15]

Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

Variants in other genes affecting JAK-STAT pathway signaling have also been reported, including JAK1, STAT3, STAT5B, and CSF2RB.[2,3]

Genomic alterations leading to NF-kappaB activation are also common in Hodgkin lymphoma.

Genomic alterations leading to NF-kappaB activation are also common in Hodgkin lymphoma.

The REL gene at chromosome 2p16.1 shows genomic gain or amplification in approximately one-third of Hodgkin lymphoma cases.[2,16]

Genomic alterations leading to NF-kappaB activation are also common in Hodgkin lymphoma.

EBV-positive Hodgkin lymphoma expresses the EBV latent membrane protein 1 (LMP1) at the cell surface. This protein acts like a constitutively activated receptor of the TNF receptor family to cause activation of the NF-kappaB pathway.[17]

Genomic alterations leading to NF-kappaB activation are also common in Hodgkin lymphoma.

Inactivating variants in genes that inhibit NF-kappaB pathway signaling, including TNFAIP3, NFKBIA, and NFKBIE, are common in Hodgkin lymphoma. Inactivation of the gene products for these genes leads to NF-kappaB pathway activation. TNFAIP3 is the most commonly altered inhibitor of NF-kappaB pathway signaling, and loss of function alterations occur by either variants or by focal 6q23.3 or arm-level 6q loss.[2,18] TNFAIP3 genomic alterations are much more common in EBV-negative Hodgkin lymphoma than in EBV-positive Hodgkin lymphoma, suggesting that LMP1 expression in EBV-positive Hodgkin lymphoma obviates the need for TNFAIP3 loss of function.[2,18]

Other genes with variants in Hodgkin lymphoma include XPO1, RBM38, ACTB, ARID1A, and GNA13.[2,3,6]

An evaluation of a large cohort of both pediatric and adult patients (N = 366) with classical Hodgkin lymphoma profiled by ctDNA revealed two molecular clusters based on variant profiles. The H1 cluster is characterized by younger age, higher mutational burden, and variants in NF-kappaB and JAK/STAT signaling. The H2 cluster is distributed more evenly across age groups, has a lower mutational burden, and more frequent somatic copy number alterations.[7]

Hodgkin lymphoma is derived from a B-cell progenitor, and HRS cells generally do not express B-cell surface antigens. HRS cells do have immunoglobulin (Ig) heavy and light chain V gene rearrangements typical of B cells.[19,20] Although Ig genes have undergone rearrangements in HRS cells, the rearrangements are nonproductive and B-cell receptor is not expressed.