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Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.

Publication ,  Journal Article
Lee, MJ; Koff, JL; Switchenko, JM; Jhaney, CI; Harkins, RA; Patel, SP; Dave, SS; Flowers, CR
Published in: Cancer
August 1, 2020

BACKGROUND: Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities. METHODS: To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort. RESULTS: Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P = .04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P < .001), MGA (19.7% vs 5.33%; P < .001), SETD2 (17.3% vs 5.17%; P < .001), TET2 (12.3% vs 5.82%; P = .029), MLL3 (KMT2C) (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016). CONCLUSIONS: Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.

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Published In

Cancer

DOI

EISSN

1097-0142

Publication Date

August 1, 2020

Volume

126

Issue

15

Start / End Page

3493 / 3503

Location

United States

Related Subject Headings

  • Young Adult
  • White People
  • Proto-Oncogene Proteins c-bcl-2
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Proteins
  • Myeloid Differentiation Factor 88
  • Mutation
  • Middle Aged
  • Male
 

Citation

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Lee, M. J., Koff, J. L., Switchenko, J. M., Jhaney, C. I., Harkins, R. A., Patel, S. P., … Flowers, C. R. (2020). Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma. Cancer, 126(15), 3493–3503. https://doi.org/10.1002/cncr.32866
Lee, Michelle J., Jean L. Koff, Jeffrey M. Switchenko, C Ileen Jhaney, R Andrew Harkins, Sharvil P. Patel, Sandeep S. Dave, and Christopher R. Flowers. “Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.Cancer 126, no. 15 (August 1, 2020): 3493–3503. https://doi.org/10.1002/cncr.32866.
Lee MJ, Koff JL, Switchenko JM, Jhaney CI, Harkins RA, Patel SP, et al. Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma. Cancer. 2020 Aug 1;126(15):3493–503.
Lee, Michelle J., et al. “Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.Cancer, vol. 126, no. 15, Aug. 2020, pp. 3493–503. Pubmed, doi:10.1002/cncr.32866.
Lee MJ, Koff JL, Switchenko JM, Jhaney CI, Harkins RA, Patel SP, Dave SS, Flowers CR. Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma. Cancer. 2020 Aug 1;126(15):3493–3503.
Journal cover image

Published In

Cancer

DOI

EISSN

1097-0142

Publication Date

August 1, 2020

Volume

126

Issue

15

Start / End Page

3493 / 3503

Location

United States

Related Subject Headings

  • Young Adult
  • White People
  • Proto-Oncogene Proteins c-bcl-2
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Proteins
  • Myeloid Differentiation Factor 88
  • Mutation
  • Middle Aged
  • Male