Prevalent homozygous deletions of type i interferon and defensin genes in human cancers associate with immunotherapy resistance

Zhenqing Ye, Haidong M Dong, Ying Li, Tao Ma, Haojie Huang, Hon Sing Leong, Jeanette E Eckel-Passow, Jean-Pierre Kocher, Han Liang, Liguo Wang

Research output: Contribution to journalArticle

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Abstract

Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy-number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the type-I interferon, a-, and b-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%–31%, median ¼ 12%; interquartile range ¼ 10%–16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P ¼ 0.0029, OR ¼ 11.8) and defensin (P ¼ 0.06, OR ¼ 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance.

Original languageEnglish (US)
Pages (from-to)3299-3308
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2018

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Defensins
Immunotherapy
Interferons
Genes
Neoplasms
Disease-Free Survival
Carcinogenesis
Genome
Exome
Interferon Type I
Atlases
Melanoma
Cell Cycle
Research Design
Biomarkers
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Prevalent homozygous deletions of type i interferon and defensin genes in human cancers associate with immunotherapy resistance. / Ye, Zhenqing; Dong, Haidong M; Li, Ying; Ma, Tao; Huang, Haojie; Leong, Hon Sing; Eckel-Passow, Jeanette E; Kocher, Jean-Pierre; Liang, Han; Wang, Liguo.

In: Clinical Cancer Research, Vol. 24, No. 14, 15.07.2018, p. 3299-3308.

Research output: Contribution to journalArticle

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abstract = "Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy-number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the type-I interferon, a-, and b-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7{\%}–31{\%}, median ¼ 12{\%}; interquartile range ¼ 10{\%}–16.5{\%}). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P ¼ 0.0029, OR ¼ 11.8) and defensin (P ¼ 0.06, OR ¼ 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance.",
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AU - Li, Ying

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AU - Leong, Hon Sing

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AU - Kocher, Jean-Pierre

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