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Germline genetic variants associated with leukocyte-genes predict tumor recurrence in breast cancer patients

View ORCID ProfileJean-Sébastien Milanese, Chabane Tibiche, Jinfeng Zou, Zhi Gang Meng, View ORCID ProfileAndre Nantel, Simon Drouin, Richard Marcotte, View ORCID ProfileEdwin Wang
doi: https://doi.org/10.1101/312355
Jean-Sébastien Milanese
1National Research Council Canada, 6100 Royalmount Ave, Montreal, Canada, H4P 2R2
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Chabane Tibiche
1National Research Council Canada, 6100 Royalmount Ave, Montreal, Canada, H4P 2R2
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Jinfeng Zou
1National Research Council Canada, 6100 Royalmount Ave, Montreal, Canada, H4P 2R2
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Zhi Gang Meng
2Department of Biochemistry & Molecular Biology, Medical Genetics, and Oncology, University of Calgary, 3330 Hospital Dr. NW, Calgary, Canada, T2N 4N1
3Chinese Academy of Agricultural Science, No. 12 Zhongguangcun South St., Haidian District, Beijing, 100086, China
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Andre Nantel
1National Research Council Canada, 6100 Royalmount Ave, Montreal, Canada, H4P 2R2
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Simon Drouin
1National Research Council Canada, 6100 Royalmount Ave, Montreal, Canada, H4P 2R2
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Richard Marcotte
1National Research Council Canada, 6100 Royalmount Ave, Montreal, Canada, H4P 2R2
4Rosalind and Morris Goodman Cancer Research Centre, McGill University, Quebec, Canada, McGill University, 1160 Pine Ave W, Montreal, Canada, H3A 1A3
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Edwin Wang
2Department of Biochemistry & Molecular Biology, Medical Genetics, and Oncology, University of Calgary, 3330 Hospital Dr. NW, Calgary, Canada, T2N 4N1
5Alberta Children’s Hospital Research Institute and Arnie Charbonneau Cancer Research Institute, University of Calgary, 3330 Hospital Dr. NW, Calgary, Canada, T2N 4N1
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  • ORCID record for Edwin Wang
  • For correspondence: edwin.wang@ucalgary.ca
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Abstract

Germline genetic variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5-10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n=755) cancer patients. Gene signatures derived from the genes containing functionally germline genetic variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n=200 and 295, P=1.4×10−3). Furthermore, we found that recurred patients possessed a higher rate of germline genetic variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients’ outcomes (or drug response) in breast cancer, other cancer types and even other complex diseases.

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Posted February 01, 2019.
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Germline genetic variants associated with leukocyte-genes predict tumor recurrence in breast cancer patients
Jean-Sébastien Milanese, Chabane Tibiche, Jinfeng Zou, Zhi Gang Meng, Andre Nantel, Simon Drouin, Richard Marcotte, Edwin Wang
bioRxiv 312355; doi: https://doi.org/10.1101/312355
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Germline genetic variants associated with leukocyte-genes predict tumor recurrence in breast cancer patients
Jean-Sébastien Milanese, Chabane Tibiche, Jinfeng Zou, Zhi Gang Meng, Andre Nantel, Simon Drouin, Richard Marcotte, Edwin Wang
bioRxiv 312355; doi: https://doi.org/10.1101/312355

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