Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells Journal Article
| Authors: | Reichel, J.; Chadburn, A.; Rubinstein, P. G.; Giulino-Roth, L.; Tam, W.; Liu, Y.; Gaiolla, R.; Eng, K.; Brody, J.; Inghirami, G.; Carlo-Stella, C.; Santoro, A.; Rahal, D.; Totonchy, J.; Elemento, O.; Cesarman, E.; Roshal, M. |
| Article Title: | Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells |
| Abstract: | Classical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. ßoglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2Mprotein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define amajor subset of cHL that hasmore uniformclinical andmorphologic features. © 2015 by The American Society of Hematology. |
| Keywords: | immunohistochemistry; adolescent; adult; child; controlled study; protein expression; aged; major clinical study; overall survival; somatic mutation; cancer staging; flow cytometry; human immunodeficiency virus infection; progression free survival; oncogene; beta 2 microglobulin; gene dosage; point mutation; cell selection; rna sequence; major histocompatibility antigen class 1; classical hodgkin lymphoma; reed sternberg cell; tumor microenvironment; molecularly targeted therapy; copy number variation; nodular sclerosis hodgkin lymphoma; indel mutation; exome; very elderly; human; male; female; priority journal; article |
| Journal Title: | Blood |
| Volume: | 125 |
| Issue: | 7 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2015-02-12 |
| Start Page: | 1061 |
| End Page: | 1072 |
| Language: | English |
| DOI: | 10.1182/blood-2014-11-610436 |
| PROVIDER: | scopus |
| PUBMED: | 25488972 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
