Original Study| Volume 23, ISSUE 3, P272-280, April 2023

Download started.


Novel Association of IGF2BP2 Gene Variants With Altered Risk of Breast Cancer and as Potential Molecular Biomarker of Triple Negative Breast Cancer

Published:December 30, 2022DOI:


      • Minor allele of rs440960, but not rs1470579, was significantly associated with breast cancer (BC).
      • Significantly higher rs4402960 T/T genotype frequency was noted in BC cases.
      • Lower rs1470579 minor allele and genotype frequencies seen in triple negative BC (TNBC) cases.
      • Both susceptible and protective 2-locus haplotypes associated with TNBC.



      Several studies documented that insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP2) contributes to carcinogenesis, and 1 report documented the association of IGF2BP2 rs4402960 with increased risk of breast cancer (BC). This study investigated the association of rs4402960 and rs1470579 IGF2BP2 variants with BC and triple negative BC (TNBC).

      Materials and Methods

      This case-control study included 488 BC patients comprising 130 TNBC and 358 non-TNBC patients, and 476 cancer-free controls. Genomic DNA was obtained from peripheral venous blood, and genotyping was done by allelic exclusion method on real-time PCR.


      The rs440960, but not rs1470579, minor allele was significantly associated with BC, and significantly higher rs4402960 T/T genotype frequency was noted in BC patients than controls; the distribution of rs1470579 genotypes were comparable between BC patients and controls. In contrast, significantly lower rs1470579 minor allele frequency, and reduced rs1470579 A/C and C/C, and rs4402960 T/T genotype frequencies were seen in TNBC cases. Among TNBC cases, rs4402960 and rs1470579 correlated with menses pattern, histological type, breastfeeding, oral contraceptive use and hormonotherapy. Among non-TNBC patients, and rs1470579 correlated significantly with breast feeding, oral contraceptive use, hormonotherapy, and nodal status; rs4402960 also correlated with menses pattern. Two-locus (rs440960-rs1470579) haplotype analysis confirmed the positive association of TC, and negative association of GC and TA haplotypes with BC, while TC and GC haplotypes were negatively associated with TNBC.


      Whereas rs440960 was positively associated with BC, both rs4402960 and rs1470579 were negatively associated with TNBC, suggesting potential diagnostic/prognostic role in BC and its complications.



      BC (breast cancer), CI (confidence interval), ER (estrogen receptor), HER/2-neu (human epidermal growth factor receptor 2), IGF2 (insulin-like growth factor-2), IGF2BP2 (insulin-like growth factor-2 mRNA-binding protein 2), LN (lymph nodes), OR (odds ratio), PR (progesterone receptor), TNBC (triple negative BC)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Loibl S
        • Poortmans P
        • Morrow M
        • Denkert C
        • Curigliano G.
        Breast cancer.
        Lancet. 2021; 397: 1750-1769
        • Bray F
        • Ferlay J
        • Soerjomataram I
        • Siegel RL
        • Torre LA
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Berrazaga Y
        • Yahyaoui Y
        • Hamdi A
        • et al.
        Breast cancer T1 in an emerging country: 325 Tunisian cases.
        Breast J. 2020; 26: 2447-2448
        • Cserni G
        • Quinn CM
        • Foschini MP
        • et al.
        Triple-negative breast cancer histological subtypes with a favourable prognosis.
        Cancers (Basel). 2021; 13: 5694
        • Ibragimova MK
        • Tsyganov MM
        • Litviakov NV.
        Molecular-genetic portrait of breast cancer with triple negative phenotype.
        Cancers (Basel). 2021; 13: 5348
        • Bianchini G
        • Balko JM
        • Mayer IA
        • Sanders ME
        • Gianni L.
        Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.
        Nat Rev Clin Oncol. 2016; 13: 674-690
        • Denkert C
        • Liedtke C
        • Tutt A
        • von Minckwitz G.
        Molecular alterations in triple-negative breast cancer-the road to new treatment strategies.
        Lancet. 2017; 389: 2430-2442
        • Lehmann BD
        • Jovanović B
        • Chen X
        • et al.
        Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection.
        PLoS ONE. 2016; 11e0157368
        • Nunnery SE
        • Mayer IA
        • Balko JM.
        Triple-negative breast cancer: breast tumors with an identity crisis.
        Cancer J. 2021; 27: 2-7
        • Barghash A
        • Helms V
        • Kessler SM.
        Overexpression of IGF2 mRNA-binding protein 2 (imp2/p62) as a feature of basal-like breast cancer correlates with short survival.
        Scand J Immunol. 2015; 82: 142-143
        • Howlader N
        • Cronin KA
        • Kurian AW
        • Andridge R.
        Differences in breast cancer survival by molecular subtypes in the United States.
        Cancer Epidemiol Biomark Prev. 2018; 27: 619-626
        • Liu Y
        • He M
        • Zuo WJ
        • Hao S
        • Wang ZH
        • Shao ZM.
        Tumor size still impacts prognosis in breast cancer with extensive nodal involvement.
        Front Oncol. 2021; 11585613
        • Curtis C
        • Shah SP
        • Chin S-F
        • et al.
        The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
        Nature. 2021; 486: 346-352
        • Messaoudi SA
        • Al Sharhan NA
        • Alharthi B
        • et al.
        Detection of genetic mutations in patients with breast cancer from Saudi Arabia using Ion AmpliSeq™ Cancer Hotspot Panel v.2.0.
        Biomed Rep. 2022; 16: 26
        • Hamilton N
        • Austin D
        • Márquez-Garbán D
        • et al.
        Receptors for insulin-like growth factor-2 and androgens as therapeutic targets in triple-negative breast cancer.
        Int J Mol Sci. 2017; 18: 2305
        • Vella V
        • Giuliano M
        • La Ferlita A
        • et al.
        Novel mechanisms of tumor promotion by the insulin receptor isoform A in triple-negative breast cancer cells.
        Cells. 2021; 10: 3145
        • Cao J
        • Yan W
        • Ma X
        • Huang H
        • Yan H.
        Insulin-like growth factor 2 mRNA-binding protein 2-a potential link between type 2 diabetes mellitus and cancer.
        J Clin Endocrinol Metab. 2021; 106: 2807-2818
        • Nemr R
        • Echtay A
        • Dashti EA
        • et al.
        Strong association of common variants in the IGF2BP2 gene with type 2 diabetes in Lebanese Arabs.
        Diabetes Res Clin Pract. 2012; 96: 225-229
        • Liu G
        • Zhu T
        • Cui Y
        • et al.
        Correlation between IGF2BP2 gene polymorphism and the risk of breast cancer in Chinese Han women.
        Biomed Pharmacother. 2015; 69: 297-300
        • Ezzidi I
        • Mtiraoui N
        • Kacem M
        • et al.
        Interleukin-10-592C/A, -819C/T and -1082A/G promoter variants affect the susceptibility to nephropathy in Tunisian type 2 diabetes (T2DM) patients.
        Clin Endocrinol (Oxf). 2009; 70: 401-407
        • Xu X
        • Yu Y
        • Zong K
        • Lv P
        • Gu Y.
        Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway.
        J Exp Clin Cancer Res. 2019; 38: 497
        • Miricescu D
        • Totan A
        • Stanescu-Spinu II
        • Badoiu SC
        • Stefani C
        • Greabu M.
        PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects.
        Int J Mol Sci. 2020; 22: 173
        • Keenan T
        • Moy B
        • Mroz EA
        • et al.
        Comparison of the genomic landscape between primary breast cancer in African American versus white women and the association of racial differences with tumor recurrence.
        J Clin Oncol. 2015; 33: 3621-3627
        • Ghali RM
        • Al-Mutawa MA
        • Al-Ansari AK
        • et al.
        Differential association of ESR1 and ESR2 gene variants with the risk of breast cancer and associated features: a case-control study.
        Gene. 2018; 651: 194-199
        • Ghali RM
        • Al-Mutawa MA
        • Ebrahim BH
        • et al.
        Progesterone receptor (PGR) gene variants associated with breast cancer and associated features: a case-control study.
        Pathol Oncol Res. 2020; 26: 141-147
        • Saidi S
        • Slamia LB
        • Mahjoub T
        • Ammou SB
        • Almawi WY.
        Association of PAI-1 4G/5G and -844G/A gene polymorphism and changes in PAI-1/tPA levels in stroke: a case-control study.
        J Stroke Cerebrovasc Dis. 2007; 16: 153-159
        • Hankó-Bauer O
        • Georgescu R
        • Coros MF
        • Boros M
        • Barsan I
        • Stolnicu S.
        Correlation between obesity and prognostic/predictive parameters with emphasis on the importance of lymph node metastases in patients with invasive breast carcinoma.
        Pol J Pathol. 2017; 68: 33-39
        • Scholz C
        • Andergassen U
        • Hepp P
        • et al.
        Obesity as an independent risk factor for decreased survival in node-positive high-risk breast cancer.
        Breast Cancer Res Treat. 2015; 151: 569-576
        • Tait S
        • Pacheco JM
        • Gao F
        • Bumb C
        • Ellis MJ
        • Ma CX.
        Body mass index, diabetes, and triple-negative breast cancer prognosis.
        Breast Cancer Res Treat. 2014; 146: 189-197
        • García-Estévez L
        • Cortés J
        • Pérez S
        • Calvo I
        • Gallegos I
        • Moreno-Bueno G.
        Obesity and breast cancer: a paradoxical and controversial relationship influenced by menopausal status.
        Front Oncol. 2021; 11705911
        • Khalis M
        • Charbotel B
        • Chajès V
        • et al.
        Menstrual and reproductive factors and risk of breast cancer: a case-control study in the Fez region, Morocco.
        PLoS One. 2018; 13e0191333
        • Jin L
        • Shen F
        • Weinfeld M
        • Sergi C.
        Insulin growth factor binding protein 7 (IGFBP7)-related cancer and IGFBP3 and IGFBP7 crosstalk.
        Front Oncol. 2020; 10: 727
        • Li J
        • Gao X
        • Zhang Z
        • et al.
        CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502-5p/KRAS and IGF2BP2/Myc axes.
        Mol Cancer. 2021; 20: 138
        • Russo VC
        • Azar WJ
        • You SW
        • Sabin MA
        • Werther GA.
        IGFBP-2: the dark horse in metabolism and cancer.
        Cytokine Growth Factor Rev. 2015; 26: 329-346
        • Hoeflich A
        • Russo VC.
        Physiology and pathophysiology of IGFBP-1 and IGFBP-2 - consensus and dissent on metabolic control and malignant potential.
        Best Pract Res Clin Endocrinol Metab. 2015; 29: 685-700
        • Bauer KR
        • Brown M
        • Cress RD
        • Parise CA
        • Caggiano V.
        Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry.
        Cancer. 2007; 109: 1721-1728
        • Chen S
        • Qiu H
        • Liu C
        • Wang Y
        • Tang W
        • Kang M.
        Relationship between IGF2BP2 and IGFBP3 polymorphisms and susceptibility to non-small-cell lung cancer: a case-control study in Eastern Chinese Han population.
        Cancer Manag Res. 2018; 10: 2965-2975
        • Qiu H
        • Wang Y
        • Kang M
        • et al.
        The relationship between IGF2BP2 and PPARG polymorphisms and susceptibility to esophageal squamous-cell carcinomas in the eastern Chinese Han population.
        Onco Targets Ther. 2017; 10: 5525-5532
        • Deng N
        • Zhou H
        • Fan H
        • Yuan Y.
        Single nucleotide polymorphisms and cancer susceptibility.
        Oncotarget. 2017; 8: 110635-110649
        • Yan B
        • Guan D
        • Wang C
        • et al.
        An integrative method to decode regulatory logics in gene transcription.
        Nat Commun. 2017; 8: 1044
        • Kasprzak A
        • Szaflarski W.
        Role of alternatively spliced messenger RNA (mRNA) isoforms of the insulin-like growth factor 1 (IGF1) in selected human tumors.
        Int J Mol Sci. 2020; 21: 6995
        • Hajjej A
        • Almawi WY
        • Hattab L
        • Hmida S.
        Anthropological analysis of Tunisian populations as inferred from HLA class I and class II genetic diversity: a meta-analysis.
        Immunol Lett. 2017; 185: 12-26
        • Chou CH
        • Chang CY
        • Lu HJ
        • et al.
        IGF2BP2 polymorphisms are associated with clinical characteristics and development of oral cancer.
        Int J Mol Sci. 2020; 21: 5662
        • Almawi WY
        • Hubail B
        • Arekat DZ
        • et al.
        Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome.
        J Assist Reprod Genet. 2015; 32: 607-614
        • Tang W
        • Chen S
        • Liu J
        • Liu C
        • Wang Y
        • Kang M.
        Investigation of IGF1, IGF2BP2, and IGFBP3 variants with lymph node status and esophagogastric junction adenocarcinoma risk.
        J Cell Biochem. 2019; 120: 5510-5518
        • Sainz J
        • Rudolph A
        • Hoffmeister M
        • et al.
        Effect of type 2 diabetes predisposing genetic variants on colorectal cancer risk.
        J Clin Endocrinol Metab. 2012; 97: E845-E851