The clinicopathological significance and drug target potential of FHIT in breast cancer, a meta-analysis and literature review

Abstract

FHIT is a bona fide tumor-suppressor gene and its loss contributes to tumorigenesis of epithelial cancers including breast cancer (BC). However, the association and clinicopathological significance between FHIT promoter hypermethylation and BC remains unclear. The purpose of this study is to conduct a meta-analysis and literature review to investigate the clinicopathological significance of FHIT methylation in BC. A detailed literature search was performed in PubMed, EMBASE, Web of Science, and Google Scholar databases. The data were extracted and assessed by two reviewers independently. Odds ratios with 95% corresponding confidence intervals were calculated. A total of seven relevant articles were available for meta-analysis, which included 985 patients. The frequency of FHIT hypermethylation was significantly increased in invasive ductal carcinoma compared to benign breast disease, the pooled odds ratio was 8.43, P<0.00001. The rate of FHIT hypermethylation was not significantly different between stage I/II and stage III/IV, odds ratio was 2.98, P=0.06. In addition, FHIT hypermethylation was not significantly associated with ER and PR status. FHIT hypermethylation was not significantly correlated with premenopausal and postmenopausal patients with invasive ductal carcinoma. In summary, our meta-analysis indicated that the frequency of FHIT hypermethylation was significantly increased in BC compared to benign breast disease. The rate of FHIT hypermethylation in advanced stages of BC was higher than in earlier stages; however, the difference was not statistically significant. Our data suggested that FHIT methylation could be a diagnostic biomarker of BC carcinogenesis. FHIT is a potential drug target for development of demethylation treatment for patients with BC.

Keywords: FHIT; drug target; meta-analysis; methylation; odds ratio; tumor suppressor gene.

Figure 1

Schematic flow diagram for selection of included studies.

Figure 2

Forest plot for FHIT hypermethylation in IDC and benign breast disease. Abbreviations: IDC, invasive ductal carcinoma; df, degrees of freedom; CI, confidence interval; M–H, Mantel–Haenszel.

Figure 3

Forest plot for FHIT hypermethylation in different stages of BC. Abbreviations: BC, breast cancer; CI, confidence interval; df, degrees of freedom; M–H, Mantel–Haenszel.

Figure 4

Forest plot for FHIT hypermethylation in ER-positive and -negative BC. Abbreviations: BC, breast cancer; CI, confidence interval; df, degrees of freedom; M–H, Mantel–Haenszel; ER, estrogen receptor.

Figure 5

Forest plot for FHIT hypermethylation in PR-positive and -negative BC. Abbreviations: BC, breast cancer; CI, confidence interval; df, degrees of freedom; M–H, Mantel–Haenszel; PR, progesterone receptor.

Figure 6

Forest plot for FHIT hypermethylation in postmenopausal and premenopausal BC. Abbreviations: BC, breast cancer; CI, confidence interval; df, degrees of freedom; M–H, Mantel–Haenszel.

Figure 7

Funnel plot for publication bias. Notes: (A) FHIT hypermethylation in IDC and benign breast disease; (B) FHIT methylation in different stages of BC; (C) FHIT hypermethylation in ER-positive and -negative BC; (D) FHIT hypermethylation in PR-positive and -negative BC; (E) FHIT hypermethylation in postmenopausal and premenopausal BC. Abbreviations: BC, breast cancer; IDC, invasive ductal carcinoma; SE, standard error; OR, odds ratio; ER, estrogen receptor; PR, progesterone receptor.