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An extra stretch of chromosome 9 that carries both of the molecules a tumour uses to switch off T cells, plus the enzyme that turns them up further. Nearly every classical Hodgkin lymphoma has it, which is why checkpoint drugs work so well there and so poorly in most other lymphomas.
The 9p24.1 amplicon contains CD274 and PDCD1LG2, the genes for the two PD-1 ligands, and JAK2. Amplifying it raises the ligands twice over, by gene dose and by JAK2-driven transcription, and JAK2 amplification also increases sensitivity to JAK2 inhibition in the laboratory. The alteration is disease-specific: it is restricted to nodular sclerosing Hodgkin lymphoma, the subtype most closely related to mediastinal large B-cell lymphoma, and to mediastinal large B-cell lymphoma itself (Green 2010).
In 108 newly diagnosed classical Hodgkin lymphomas evaluated by fluorescence in situ hybridisation, 97% had concordant alterations of both loci: polysomy in 5 of 108, copy gain in 61 of 108 and amplification in 39 of 108, and higher-level gain predicted shorter progression-free survival (Roemer 2016). Alongside it, recurrent CIITA fusions, found in 38% of primary mediastinal B-cell lymphomas and 15% of classical Hodgkin lymphomas across 263 B-cell lymphomas, lower MHC class II on the tumour cell and place the ligands under new promoters (Steidl 2011).
This is the clearest genetic explanation in oncology for why one disease answers checkpoint blockade: PD-1 blockade gave an objective response in 20 of 23 heavily pre-treated Hodgkin patients, 87%, most of whom had already failed both autologous transplant and brentuximab vedotin (Ansell 2015). What predicts complete remission within that group is not MHC class I but MHC class II expression on the Hodgkin and Reed-Sternberg cells, which suggests the effector is a CD4 T cell (Roemer 2018).
Nobody is tested for this before being given a checkpoint drug for Hodgkin lymphoma, because almost every case has it. It is the reason these drugs work in Hodgkin lymphoma when they do very little in most other lymphomas, and that is worth knowing when comparing treatments between diseases.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
Fluorescence in situ hybridisation on the tumour cells with probes for the 9p24.1 locus and a chromosome 9 centromere control, graded as polysomy, copy gain or amplification by the ratio. It is done on the malignant cells specifically, because in Hodgkin lymphoma they are a small minority of the tissue and a bulk assay would measure the infiltrate instead.
“Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]).”
Roemer et al., Journal of Clinical Oncology 2016No approval uses this readout as a threshold. It is defined by Roemer et al., J Clin Oncol 2016: PD-L1 and PD-L2 genetic alterations in 108 classical Hodgkin lymphomas.
Shares Cytogenetics and FISH, FISH / ISH (in situ hybridisation), Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Cytogenetics and FISH, FISH / ISH (in situ hybridisation), Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.
Shares Non-Hodgkin lymphoma (all types) and the tags biomarker, lymphoma.