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IRS2
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Interpretation 239
Tier 3
IRS2
Variants
IRS2 copy number gain
Primary Sites
Colon
Gall Bladder
Brain
Tumor Types
Adenocarcinoma
Cholangiocarcinoma
Glioblastoma
Interpretation

IRS1 and IRS2 are the key protein effectors for transmitting insulin signals from the insulin-like growth factor receptor to the nucleus via the PI3K / AKT / mTOR pathway. IRS2 has been previously noted to be recurrently focally amplified in several anecdotal studies across multiple cancer types (colorectal cancer PMID: 23594372, cholangiocarcinoma PMID:26684807, glioblastoma PMID: 14655756, rhabdomyosarcoma PMID: 23578105), suggesting that this could be a "driver" alteration in a subset of cancer.. IRS2 amplifications have also been associated with sensitivity to the insulin receptor inhibitor BMS-754807 in colorectal cancer cell lines (PMID: 25527633). There is no direct evidence to connect IRS2 amplification status with sensitivity to any targeted therapy regimen in patients; however, an attractive hypothesis is that tumors harboring IRS2 amplifications could be sensitive to drugs targeting insulin signaling, PI3K, AKT, and mTOR. Drug sensitivity and exome sequencing data from colorectal patient derived tumor xenografts have associated IRS2 copy gains with sensitivity to anti-EGFR therapies (PMID: 26416732).

Citations
  1. Day E, et al. IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer. Int J Exp Pathol 2013;94(3):203-11
  2. Liu TT, et al. Recurrent Amplification at 13q34 Targets at CUL4A, IRS2, and TFDP1 As an Independent Adverse Prognosticator in Intrahepatic Cholangiocarcinoma. PLoS One 2015;10(12):e0145388
  3. Knobbe CB, et al. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 2003;13(4):507-18
  4. Nishimura R, et al. Characterization of genetic lesions in rhabdomyosarcoma using a high-density single nucleotide polymorphism array. Cancer Sci 2013;104(7):856-64
  5. Huang F, et al. IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. Mol Cancer Ther 2015;14(2):620-30
  6. Bertotti A, et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature 2015;526(7572):263-7
Last updated: 2016-04-05 17:02:32 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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