Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

Abstract

The insulin/insulin-like growth factor pathway is involved in breast and colorectal cancer (CRC) development. In the present study, we analyzed the coding region and short intron-exon borders of the insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) genes in 12 cell lines derived from breast cancer (BC), 14 cell lines derived from CRC and 33 primary CRCs. The nucleotide variants identified in BC were 3 in IRS-1, 1 of which (p.Arg267Cys) was novel and with a pathogenic potential as predicted by in silico analysis and 6 in IRS-2. Twenty-one variants in IRS-1 and 18 in IRS-2 were identified in the CRC samples. These included 11 novel IRS-1 variants detected exclusively in CRCs, which included 5 missense (p.Pro559Leu, p.Gln655His, p.Asp1014Gly, p.Asp1181His and pPro1203Ser) with a pathogenic potential as predicted by in silico analysis, 2 frameshifts predicted to generate a truncated protein, 1 splice-site mutation and 3 silent variants. In the CRC samples we also identified 7 novel IRS-2 variants, including 4 missense variants, which included 2 (p.Asp782Asn and p.Gly1230Ser) with a pathogenic potential as predicted by in silico analysis, 2 frame insertion mutations and 1 silent variant. Most of the novel IRS-1 and IRS-2 variants may be involved in the modulation of IRS-1 or IRS-2 functions and could be relevant to breast and colorectal tumorigenesis.

The effects of genetic variants related to insulin metabolism pathways and the interactions with lifestyles on colorectal cancer risk

“…IRS1 and a single member of the Akt family, Akt2, are important signaling molecules related to a diabetic phenotype such as IR; at the genomic level, each is amplified in various cancers, including CRC 11,39,40 . The IRS1 and AKT2 genes are thus key components of this pathway, but studies of the association of their genetic variants with CRC have been limited and conflicted 11,14,[40][41][42][43][44] . For example, the IRS1 rs1801278 G (C in our study) allele has higher 43,44 , inverse 41 , or no 11,14 association with CRC risk.…”

Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial

“…IRS1 and IRS2 polymorphisms have also been independently associated with increased CRC risk. In particular carriers of IRS1 rs1801278 T/- genotype showed higher incidence of CRC, while patients with IRS2 rs1805097 C/T genotype had significantly reduced the risk of developing CRC 13, 14 .…”

“…In particular carriers of IRS1 rs1801278 T/-genotype showed higher incidence of CRC, while patients with IRS2 rs1805097 C/T genotype had significantly reduced the risk of developing CRC. 13,14 IGF-1R is frequently overexpressed in human colon cancer cells 15 and has been related to the promotion of growth and malignant transformation of adenomatous polyps 16 and to the development of distant metastases in murine models. The activation of insulin/IGF-dependent pathways has been identified as a possible mechanism of CRC resistance to conventional and targeted therapeutic agents and in particular to anti-EGFRs.…”

The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy

“…Esposito et al have also analyzed the coding region and short intron-exon borders of both IRS-1 and IRS-2 in 14 CRC cell lines and 33 primary specimens. They identified 21 IRS-1 variants and 18 IRS-2 variants with 7 novel IRS-2 variants, including 4 missenses, 2 in-frame insertion mutations, and 1 silent variant ( 21 ). If and how these variants may be involved in the modulation of IRS-2 function in colorectal tumorigenesis remains to be established.…”