The Loss of Heterozygosity of FHIT Gene in Sporadic Breast Cancer


  • Lisiane Silveira Zavalhia Research Laboratory in Pathology, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Brazil
  • Andrea Pires Souto Damin Department of Gynecology and Obstetrics of Federal University, Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
  • Grasiela Agnes Research Laboratory in Molecular Biology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rio Grande do Sul, Brazil
  • Aline Weber Research Laboratory in Pathology, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Brazil
  • Taís Frederes Kramer Alcalde Research Laboratory in Pathology, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Brazil
  • Laura Marinho Dorneles Research Laboratory in Pathology, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Brazil
  • Guilherme Watte Department of Respiratory Medicine and Thoracic Surgery, Irmandade da Santa Casa de Misericordia de Porto Alegre, Rio Grande do Sul, Brazil
  • Adriana Vial Roehe Department of Pathology, Graduate Programa in Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil



The loss of heterozygosity (LOH) is a genetic event that can change gene function. FHIT is a potential tumor suppressor gene.  Although the precise FHIT molecular mechanism of action is not well understood, evidences suggest that Fhit protein reduced levels are involved in mammary carcinogenesis.  The aim of this study was to investigate if FHIT LOH could influence on sporadic breast cancer (BC) biological behavior, through its association with prognostic factors for sporadic BC.

Tumor tissue and peripheral blood samples were analyzed using the microsatellite marker D3S1300. The findings were associated with clinicopathological parameters including overall survival. LOH was detected in 31.1%(52/167) of the informative BC’ cases. Considering clinical and pathological characteristics we have found no significant association with FHIT LOH status. The mean follow-up time was 80 months. After the Cox regression analysis two parameters remained associated with BC’s risk of death: TNM stage III and IV - HR = 3.74(95% CI, 1.16-12.1) P=0.027 and disease relapse HR = 3.14(CI 95% 1.26-7.80) P =0.014. 

This study shows that FHIT LOH by itself is not a prognostic factor for sporadic BC.  Further researches are required to elucidate the functional role of FHIT LOH concerning to BC. 


Breast cancer, D3S1300, LOH, Survival, Loss of heterozygosity


[1] 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 (2018) 394-424. DOI: 10.3322/caac.21492.

[2] Pedraza V, Gomez-Capilla JA, Escaramis G, et al. Gene expression signatures in breast cancer distinguish phenotype characteristics, histologic subtypes, and tumor invasiveness, Cancer. 116 (2010) 486-496. DOI: 10.1002/cncr.24805.

[3] Weigelt B, Baehner FL, Reis-Filho JS. The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: A retrospective of the last decade, J Pathol. 220 (2010) 263-280. DOI: 10.1002/path.2648.

[4] Glover TW, Stein CK. Chromosome breakage and recombination at fragile sites, Am J Hum Genet. 43 (1988) 265-273.

[5] Pekarsky Y, Palamarchuk A, Huebner K, Croce CM. Fhit as tumor suppressor: Mechanisms and therapeutic opportunities, Cancer Biol Ther. 1 (2002) 232-236. DOI: 10.4161/cbt.73.

[6] Lasko D, Cavenee W, Nordenskjold M. Loss of constitutional heterozygosity in human cancer, Annu Rev Genet. 25 (1991) 281-314. DOI: 10.1146/

[7] Ahmadian M, Wistuba II, Fong KM, et al. Analysis of the fhit gene and fra3b region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands, Cancer Res. 57 (1997) 3664-3668.

[8] de Oliveira MM, de Oliveira SF, Lima RS, et al. Differential loss of heterozygosity profile on chromosome 3p in ductal and lobular breast carcinomas, Hum Pathol. 43 (2012) 1661-1667. DOI: 10.1016/j.humpath.2011.12.008.

[9] Santos SC, Cavalli LR, Cavalli IJ, Lima RS, Haddad BR, Ribeiro EM. Loss of heterozygosity of the brca1 and fhit genes in patients with sporadic breast cancer from southern brazil, J Clin Pathol. 57 (2004) 374-377. DOI: 10.1136/jcp.2003.013490.

[10] Ingvarsson S, Sigbjornsdottir BI, Huiping C, Jonasson JG, Agnarsson BA. Alterations of the fhit gene in breast cancer: Association with tumor progression and patient survival, Cancer Detect Prev. 25 (2001) 292-298.

[11] Rabelo RA, Antunes LM, Etchebehere RM, et al. Loss of heterozygosity in the fragile histidine triad (fhit) locus and expression analysis of fhit protein in patients with breast disorders, Clin Exp Obstet Gynecol. 40 (2013) 89-94.

[12] van Houten VM, Tabor MP, van den Brekel MW, et al. Molecular assays for the diagnosis of minimal residual head-and-neck cancer: Methods, reliability, pitfalls, and solutions, Clin Cancer Res. 6 (2000) 3803-3816.

[13] Negrini M, Monaco C, Vorechovsky I, et al. The fhit gene at 3p14.2 is abnormal in breast carcinomas, Cancer Res. 56 (1996) 3173-3179.

[14] Croce CM, Sozzi G, Huebner K. Role of fhit in human cancer, J Clin Oncol. 17 (1999) 1618-1624. DOI: 10.1200/JCO.1999.17.5.1618.

[15] Yang Q, Yoshimura G, Suzuma T, et al. Clinicopathological significance of fragile histidine triad transcription protein expression in breast carcinoma, Clin Cancer Res. 7 (2001) 3869-3873.

[16] Campiglio M, Pekarsky Y, Menard S, Tagliabue E, Pilotti S, Croce CM. Fhit loss of function in human primary breast cancer correlates with advanced stage of the disease, Cancer Res. 59 (1999) 3866-3869.

[17] Ingvarsson S, Agnarsson BA, Sigbjornsdottir BI, et al. Reduced fhit expression in sporadic and brca2-linked breast carcinomas, Cancer Res. 59 (1999) 2682-2689.

[18] Kollias J, Man S, Marafie M, et al. Loss of heterozygosity in bilateral breast cancer, Breast Cancer Res Treat. 64 (2000) 241-251. DOI: 10.1023/a:1026575619155.

[19] Man S, Ellis IO, Sibbering M, Blamey RW, Brook JD. High levels of allele loss at the fhit and atm genes in non-comedo ductal carcinoma in situ and grade i tubular invasive breast cancers, Cancer Res. 56 (1996) 5484-5489.

[20] Silva Soares EW, de Lima Santos SC, Bueno AG, et al. Concomitant loss of heterozygosity at the brca1 and fhit genes as a prognostic factor in sporadic breast cancer, Cancer Genet Cytogenet. 199 (2010) 24-30. DOI: 10.1016/j.cancergencyto.2010.01.019.

[21] Huebner K, Croce CM. Fra3b and other common fragile sites: The weakest links, Nat Rev Cancer. 1 (2001) 214-221. DOI: 10.1038/35106058.

[22] Barrett JC. Mechanisms of multistep carcinogenesis and carcinogen risk assessment, Environ Health Perspect. 100 (1993) 9-20. DOI: 10.1289/ehp.931009.

[23] Burke L, Khan MA, Freedman AN, et al. Allelic deletion analysis of the fhit gene predicts poor survival in non-small cell lung cancer, Cancer Res. 58 (1998) 2533-2536.

[24] Petursdottir TE, Hafsteinsdottir SH, Jonasson JG, et al. Loss of heterozygosity at the fhit gene in different solid human tumours and its association with survival in colorectal cancer patients, Anticancer Res. 22 (2002) 3205-3212.

[25] Capuzzi D, Santoro E, Hauck WW, et al. Fhit expression in gastric adenocarcinoma: Correlation with disease stage and survival, Cancer. 88 (2000) 24-34.

[26] Gatalica Z, Lele SM, Rampy BA, Norris BA. The expression of fhit protein is related inversely to disease progression in patients with breast carcinoma, Cancer. 88 (2000) 1378-1383.

[27] Yang Q, Nakamura M, Nakamura Y, et al. Two-hit inactivation of fhit by loss of heterozygosity and hypermethylation in breast cancer, Clin Cancer Res. 8 (2002) 2890-2893.

[28] Knudson AG, Jr. Mutation and cancer: Statistical study of retinoblastoma, Proc Natl Acad Sci U S A. 68 (1971) 820-823. DOI: 10.1073/pnas.68.4.820.

[29] Hayashi S, Tanimoto K, Hajiro-Nakanishi K, et al. Abnormal fhit transcripts in human breast carcinomas: A clinicopathological and epidemiological analysis of 61 japanese cases, Cancer Res. 57 (1997) 1981-1985.

[30] Martinez A, Walker RA, Shaw JA, Dearing SJ, Maher ER, Latif F. Chromosome 3p allele loss in early invasive breast cancer: Detailed mapping and association with clinicopathological features, Mol Pathol. 54 (2001) 300-306. DOI: 10.1136/mp.54.5.300.


How to Cite

Zavalhia, L. S., Damin, A. P. S., Agnes, G., Weber, A., Alcalde, T. F. K., Dorneles, L. M., Watte, G., & Roehe, A. V. (2021). The Loss of Heterozygosity of FHIT Gene in Sporadic Breast Cancer. Journal of Oncology Research, 3(2), 33–39.