The significant association between IGF-1, IGF-2, IGFBP-2 and -3

The results of an epidemiological study showing that higher levels of IGF-1 are
correlated with an elevated risk of gynaecological cancers and ovarian tumours, particularly
6. The tissue of ovarian cancer has been shown to exhibit a high IGF-1 and low IGFBP
expression. This finding has been reported in the 90s of the 20th century by Karasik et al.
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(1994) and Kanethy et al. (1996) 17-18. Similar data were obtained by Dursun et al.(2005)
who revealed a significantly higher IGF-1 and IGFBP-3 serum level (p=0.01) in women under
the age of 50 who underwent surgery due to serous ovarian cancer 19. A significant
correlation between IGF-1 serum levels and ovarian cancer risk has also been reported in the
group of younger than 55 age women, by Lukanova et al.(2002) 20. However, there are also
several studies presenting a significantly lower IGF-1 serum levels in patients with malignant
ovarian tumours than in controls 21. Another massive study involving a group of 222 cases
and 5999 controls have reported no significant association between IGF-1, IGF-2, IGFBP-2
and -3 levels with ovarian cancer risk 22.
A meta-analysis of published studies concerning the association between circulating IGF-1
level and ovarian cancer risk was conducted by Li et al. (2016) 23. Five eligible studies were
included in the meta-analysis, which involved a total of 2,028 cases of ovarian cancer and
4,625 controls. Meta-analysis of 5 studies showed that high circulating IGF-1 level was
significantly associated with a decreased risk of ovarian cancer (OR = 0.84, 95% CI 0.74-
0.97, p= 0.013). High circulating IGF-1 level was still associated with a decreased risk of
ovarian cancer (OR = 0.83, 95%CI 0.72-0.95, p= 0.007) after adjusting for heterogeneity. An
analysis by age revealed that circulating IGF-1 level was not connected with ovarian cancer
risk and older than 55 years. However, after adjusting for heterogeneity, high circulating IGF1
level went with decreased ovarian cancer risk in women younger than 55 years old (OR =
0.82, 95%CI 0.72-0.94, P = 0.004). Ose et al. (2015) hypothesised that circulating IGF-I
would be associated with ovarian cancer subtypes provided the varied expression of IGF-I in
low- and high-grade serous tumours 4. Moreover, IGF-1 is overexpressed in low-grade
serous ovarian cancer cell lines (i.e., type I), which were more responsive to IGF-I stimulation
and IGF- IR inhibition compared with high-grade serous ovarian cancer cell lines (i.e., type
II) 25. Ose et al.(2015) did not observe the hypothesised associations; however, we had the
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small sample number in some subgroups (i.e., low-grade serous tumours, n 1?4 35) 4. In
2017 the results of a collaborative re-analysis from Ovarian Cancer Cohort Consortium have
addressed the association between doubling of IGF-I concentration and risk of EOC
ORlog2=0.82; CI 0.72-0.93. Ose et al.(2017)observed no heterogeneity by tumor
characteristics (e.g., histology, p het=0.62), menopausal status at blood collection (p
het=0.79), or age at diagnosis (p het=0.60) 5. These authors suggested that IGF-1
concentrations are inversely associated with EOC risk independent of histological phenotype
5.
In the FP6 European Project “OVCAD”, 275 consecutive primary epithelial ovarian cancers
were included from the patients after radical cytoreductive surgery and platinum-based
chemotherapy 25. The authors analysed the predictive and prognostic role of circulatory
IGF-1 in these patients and reported that an increased plasma IGF-1 levels were significantly
more frequent in well-differentiated epithelial OC. It has also been found a weak correlation
between IGF-1 levels and CA-125 in patients with serous epithelial OC. No association
between IGF-1 expression and either clinicopathological data was observed 25.
Other alterations of IGF system components in ovarian cancers
In 2011 Pearce et al. (2011) have presented the results of the multicenter study of white, nonHispanic
women 26. The IGF implication in ovarian carcinogenesis has been analysed. A
control group and a study group included respectively, 1880 and 1456 patients. A study group
consisted of 1135 patients with invasive epithelial ovarian carcinoma and 321 patients with
borderline ovarian tumours. The results have not confirmed the relationship between IGF-1,
IGFBP-1 and IGFBP-3 levels and the risk of epithelial ovarian cancer development. However,
it has been shown that the tag single- nucleotide polymorphisms (t-SNPs) in IGF-2 gene may
significantly increase the development of epithelial ovarian cancer (p<0.05). Genotyping was performed in 3216 additional non-Hispanic white cases and 5382 additional controls. It has 24 been reported that rs4320932 polymorphism is correlated with a 13% decreased the risk of ovarian cancer (95% CI 0.81-0.93, p-trend=7.4x10-5). In turn, it has been shown that the inactivating germline mutation with BRCA1 and BRCA2 are detected in a large proportion of families with ovarian cancer27. These mutation carriers have an increased lifetime risk of developing ovarian cancer (16-64%)28. Brokaw et al. (2007) have presented important study. They analysed the IGF-1 mRNA expression and IGFBP levels in patients with epithelial ovarian cancer and reported that high IGF1mRNA and IGFBP were associated with risk of disease progression 29. Another study by Spentzos et al. (2007) has described that IGFBP-4 and IGF-2R gene expression were inversely associated with patient survival 30. In turn, Tian et al. (2016) using a mass-action kinetic model- an immortalized ovarian cancer cell line- have proven that IGF-2R may be involved in the regulation of the activity of IGF-1R in different conditions and that due to their high expression levels, IGFBPs are dominant in regulating IGF network activation 31. We have found an association of serum IGF- 1 levels and polymorphism in the CA repeat in the 5' promoter region of IGF 1. IGF-1 was positively correlated with IGFBP-3 in the MSS and the MSI-H groups. Circulating and tissue IGF-1 levels were lower in women who carried (CA)19 repeat alleles (MSS IGF-1 genotype) compared to those who did not (MSI-L and MSI-H genotypes). It indicates that lack of the (CA)19 allele is associated with a higher incidence of ovarian cancer. Cleveland et al. (2006) reported that IGF-1 genotypes which include alleles with fewer than (CA)19 repeats appear to be positively correlated with increased risk of breast cancer 32. Other studies have also found an association between the number of IGF-1 CA repeat and breast cancer risk, while other have not 33-35. Zecevic et al. (2006) suggest that IGF-1 variant genotypes modify the risk of hereditary forms of cancer 36. The immunohistochemical study indicated that in tissues with a genotype other than CA 19 the number of IGF-1 expressing cells was significantly higher. Above results confirm our 25 previous findings that IGF-1 genotypes different than (CA)19 are responsible for higher levels of IGF-1 in tissues and probably in autocrine stimulation of cancer development. However, ovarian cancer, like all cancers, is a multifactorial disease arising from multiple conditions that interact in complex ways. In conclusion, the present study suggests that genetic variations of IGF(CA)19 gene polymorphisms may influence ovarian cancer risk in Caucasian women. Ongoing investigations will add to the long-term study group of women and give more strength to the present study. Further basic and clinical research studies, also at molecular levels, are needed to better clarify the functional role of this polymorphism and the complex relationships between the IGF-1 axis, IGF(CA)19 polymorphism and ovarian cancer risk.