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Gene expression analysis reveals a strong signature of an interferon-induced pathway in childhood lymphoblastic leukemia as well as in breast and ovarian cancer

Abstract

On the basis of epidemiological studies, infection was suggested to play a role in the etiology of human cancer. While for some cancers such a role was indeed demonstrated, there is no direct biological support for the role of viral pathogens in the pathogenesis of childhood leukemia. Using a novel bioinformatic tool that alternates between clustering and standard statistical methods of analysis, we performed a ‘double-blind’ search of published gene expression data of subjects with different childhood acute lymphoblastic leukemia (ALL) subtypes, looking for unanticipated partitions of patients, induced by unexpected groups of genes with correlated expression. We discovered a group of about 30 genes, related to the interferon response pathway, whose expression levels divide the ALL samples into two subgroups; high in 50, low in 285 patients. Leukemic subclasses prevalent in early childhood (the age most susceptible to infection) are over-represented in the high-expression subgroup. Similar partitions, induced by the same genes, were found also in breast and ovarian cancer but not in lung cancer, prostate cancer and lymphoma. About 40% of breast cancer samples expressed the ‘interferon-related’ signature. It is of interest that several studies demonstrated mouse mammary tumor virus-like sequences in about 40% of breast cancer samples. Our discovery of an unanticipated strong signature of an interferon-induced pathway provides molecular support for a role for either inflammation or viral infection in the pathogenesis of childhood leukemia as well as breast and ovarian cancer.

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Abbreviations

ALL:

acute lymphoblastic leukemia

IIG:

interferon-inducible genes

CTWC:

coupled two-way clustering

ATL:

adult T-cell leukemia

HTLV:

human T-cell lymphotropic viruses

TNoM:

threshold number of misclassifications

EBV:

Epstein–Barr virus

SPC:

superparamagnetic clustering

FDR:

false discovery rate

MMTV:

mouse mammary tumor virus

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Acknowledgements

We thank Dr Sema Sirma for her technical work and the patients and their families for their contribution. This project was supported by grants from the Israel Academy of Sciences and Humanities, the Ridgefield Foundation, the Minerva Foundation, the Germany-Israel Science Foundation (GIF), the Istanbul University Reseach Fund and the Turkish Society of Hematology. We are grateful to the Arison family for their donation to the Center for DNA Chips in the Pediatric Oncology Department, The Chaim Sheba Medical Center.

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Correspondence to Gideon Rechavi or Eytan Domany.

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Einav, U., Tabach, Y., Getz, G. et al. Gene expression analysis reveals a strong signature of an interferon-induced pathway in childhood lymphoblastic leukemia as well as in breast and ovarian cancer. Oncogene 24, 6367–6375 (2005). https://doi.org/10.1038/sj.onc.1208797

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