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Loss of Fragile Histidine Triad Expression in Colorectal Carcinomas and Premalignant Lesions^{1 ,3}

Departments of Pathology [X. P. H., J. E. W., T. G. P., G. T. M., T. P. P.] and Epidemiology and Biostatistics [J. S. R.], Case Western Reserve University School of Medicine and Cancer Center, Cleveland, Ohio 44106, and Academic Department of Pathology, St Mark’s Hospital, Harrow HA1 3UJ, United Kingdom [I. C. T.]

	ABSTRACT

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Abnormal expression of the fragile histidine triad (FHIT) candidate tumor suppressor gene has been observed in a variety of human tumors, but little is known about its expression during colorectal tumorigenesis. Sections of 70 aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13 metastatic lesions were evaluated immunohistochemically for Fhit expression. All normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas showed a marked loss or absence of Fhit expression. The proportion of carcinomas with reduced expression showed an increasing trend (a) with decreasing differentiation and (b) in tumors with metastases (62%) compared with tumors without metastases (38%). The proportion of metastatic lesions (12 of 13) with reduced expression of Fhit was even greater. Although only a small proportion of ACF and adenomas showed a reduction of Fhit expression, the reduced expression of Fhit was strongly associated with the degree of dysplasia in both ACF (P = 0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in a small proportion of colonic precancerous lesions and in increased proportions of primary and metastatic colorectal cancers suggest that Fhit plays a role in the development and progression of some colon carcinomas.

	Introduction

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The FHIT gene has been cloned recently and mapped to chromosomal region 3p14.2 (1) . It spans not only the t(3:8)(p14.2;q24) translocation breakpoint found in familial renal cell carcinoma but also the most common human fragile site, FRA3B (2) . Abnormalities in the FHIT gene and/or its expression have been identified in a variety of human cancer cell lines and tumor tissues including lung (3 , 4) , breast (5) , head and neck (6) , esophageal (7 , 8) , gastric (9) , pancreatic (10) , renal (11) , and cervical (12) cancer. Aberrant protein expression and allelic deletion of FHIT in lung cancer are associated with smoking history and prognosis (3 , 4) . The finding of decreased expression of Fhit in 93% of precancerous lesions of the lung suggested that this gene might be used as an intermediate biomarker for the early diagnosis and/or prevention of lung cancer (4) . A few studies have evaluated the FHIT gene in colorectal cancer, but some of the data are conflicting. Ohta et al. (2) reported three of eight primary colon tumors with aberrant FHIT transcripts, and Kastury et al. (13) found nearly 50% of colorectal cancers with loss of heterozygosity. In contrast, Thiagalingam et al. (14) suggested that "FHIT is inactivated by an unusual mechanism or that it plays a role in relatively few colorectal tumors" because they found (a) no somatic point mutations detected by sequence analysis of the complete coding regions, and (b) 29 of 31 colorectal cancers exhibited normal mRNA transcripts. Photomicrographs of Fhit protein expression in colon carcinomas have been published previously (1) , but there is no detailed investigation of Fhit protein expression during colorectal tumorigenesis. Colon cancer, like lung cancer, is thought to be induced by carcinogens; therefore, it is imperative to determine whether FHIT plays a role in this second most common cause of cancer deaths in the United States (15) . In this study of 84 colorectal carcinomas, 55 adenomas, and 70 ACF,³ we now report that Fhit protein expression was altered in a high proportion of colorectal carcinomas and metastatic lesions. Although only a small proportion of adenomas and ACF had reduced expression of Fhit, this loss of Fhit expression was strongly correlated with dysplasia.

	Materials and Methods

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Specimens.
Paraffin-embedded sections of 55 colorectal adenomas and 53 carcinomas were obtained from the Academic Department of Pathology, St Mark’s Hospital (London, United Kingdom). All of the remaining tissues were obtained from the Western division of the Cooperative Human Tissue Network of the National Cancer Institute located at Case Western Reserve University. These tissues included 31 additional carcinomas and 70 ACF; 58 ACF were from 33 patients with sporadic colon cancer, and 12 ACF were from 4 patients with FAP. The cancers were staged by Dukes’ criteria. When distant metastases were present, we classified the tumor as stage D. Of the 31 patients with carcinomas, 12 were Dukes’ stage C or D. Metastatic lesions including 3 from liver and 10 from lymph nodes were obtained from surgically resected tissue from these patients.

One of the adenomas was from a patient with a history of FAP, the remaining 54 adenomas were from patients with an average age of 58.9 ± 11.4 years (28 males and 26 females). Three carcinomas were from FAP patients; the remaining 81 carcinomas were from patients with an average age of 66.3 ± 13.8 years (44 males and 37 females). The sporadic colon cancer patients with ACF used in this study had an average age of 70.9 ± 12.9 years (17 males and 16 females).

Immunohistochemical Analysis.
Formalin-fixed paraffin-embedded sections were cut at 5 µm and placed on 3-aminopropyltriethoxysilane (Sigma, St Louis, MO)-coated slides or Superfrost/Plus slides (Fisher Scientific, Pittsburgh, PA). One section was stained with H&E and used for histological classification, and the others were used for immunostaining.

Slides were deparaffinized in xylene twice for 7 min, rehydrated through graded ethanols to distilled water, and heated in 0.01 M citrate buffer (pH 6.0) in a pressure cooker for 3 min after reaching full pressure for freshly cut slides or slides kept at 4°C. The time was increased to 7 min for slides kept for several years at room temperature. The sections were incubated for 15 min in a blocking solution containing 10% normal goat serum in PBS [0.01 M phosphate (pH 7.4), 0.137 M NaCl] and then incubated for 1 h at 37°C in a humidified chamber with rabbit polyclonal anti-glutathione S-transferase-Fhit fusion protein antibodies (Zymed Laboratories Inc., South San Francisco, CA) diluted 1:200 in blocking solution. The sections were rinsed in PBS and incubated for 30 min with biotinylated goat antirabbit IgG (Vector Laboratories, Burlingame, CA) diluted 1:200 in blocking solution. To block endogenous peroxidase activity, the slides were immersed in 3% hydrogen peroxide in 30% methanol for 10 min. After washing in distilled water, the sections were then incubated for 30 min in streptavidin-biotinylated horseradish peroxidase complex (Amersham, Arlington Heights, IL) diluted 1:100 in blocking solution. 3,3'-Diaminobenzidine (Sigma) was used as the chromogen. Slides were counterstained for 3 min with 0.1% methyl green and covered with 50% Clearium/50% xylene (Surgipath Medical Industries, Inc., Richmond, IL). Normal colonic epithelium was used as a positive control for every lesion, whereas the primary antibody was replaced by normal rabbit serum IgG with a similar dilution for a negative control.

Evaluation of Score.
Both the extent and intensity of immunopositivity were considered when scoring Fhit protein expression. The extent of positivity was scored as follows: 0, <5%; 1, >5–25%; 2, >25–50%; 3, >50–75%; and 4, >75% of the colonic epithelial cells in the respective lesions. The intensity was scored as follows: 0, negative; 1+, weak; 2+, moderate; and 3+, as strong as normal mucosa. The final score was obtained by multiplying the extent of positivity and intensity scores, producing a range from 0 to 12 (16) . Scores 9–12 were defined as preserved or strong staining pattern because there was little difference compared with normal mucosa, scores 0–4 were defined as markedly reduced or lost expression, and scores 6–8 were defined as intermediate staining pattern.

Statistical Analyses.
Fisher’s exact test (two-sided), McNemar’s ² test with continuity correction, and the Cochran-Armitage test for trends in proportions were used to assess the associations between Fhit expression and pathological data (17) . A P < 0.05 was considered significant, except when multiple analyses were done on the same data, and the Bonferonni correction was used to adjust for the multiple testing.

	Results

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Fhit Expression in Normal Mucosa and Carcinomas.
All normal colonic epithelium showed strong cytoplasmic expression of Fhit protein from the basal cells to the luminal differentiated cells (Fig. 1A) ; these served as an internal control. Some stromal cells, such as macrophages, also stained with Fhit antibodies. Fhit protein expression was retained (Fig. 1B) in 33 of 84 (39%) carcinomas, was intermediate or heterogeneous in 14 carcinomas (17%), and was markedly reduced or absent (Fig. 1C) in 37 of 84 (44%) carcinomas (Table 1) . The proportion of carcinomas with reduced expression of Fhit protein showed an increasing trend (² = 5.76, df = 1, P = 0.016) from 2 of 10 (20%) well-differentiated cancers to 30 of 68 (44%) moderately differentiated cancers to 5 of 6 (83%) poorly differentiated cancers (Table 1) . A similar trend was observed with Dukes’ stage 24 of 63 (38%) Dukes’ stage A and B cancers had reduced expression of Fhit compared with 13 of 21 (62%) Dukes’ stage C and D cancers (² = 3.68, df = 1, P = 0.055). However, no overall associations were found between Fhit expression and either the degree of differentiation or Dukes’ stage (Table 1) .

View larger version (121K): [in this window] [in a new window]   Fig. 1. Expression of Fhit protein by immunohistochemical staining of human colonic specimens embedded in paraffin. A, normal colonic epithelium with strong expression of Fhit protein from the bottom to the top of the crypts, x50; B, colon carcinoma with strong cytoplasmic expression of Fhit protein, x200; C, colon carcinoma with weak expression of Fhit protein, x120; D, metastatic colon cancer lacking Fhit expression from the same patient whose primary tumor is illustrated in B, x120; E, H&E-stained section of an adenoma with varying degrees of dysplasia; an asterisk (*) marks the same gland here and in F, x50; F, heterogenous expression of Fhit in the same adenoma as in E, x50; G, low-power view of a H&E-stained section of an ACF marked with yellow ink and arrows at the top, x50; H, low-power view of the same ACF marked with arrows showing a marked reduction of Fhit expression compared with Fhit expression in the normal glands adjacent and below it, x50; I, higher magnification of the same ACF as in G marked with arrows, x120; J, higher magnification of the same ACF marked with arrows showing a marked reduction of Fhit expression in the ACF, x120.

Fhit Expression in Premalignant Lesions: Adenomas and ACF.
For the 55 adenomas, there was an association (P = 0.0085, Fisher’s exact test) between the loss of Fhit expression and the degree of dysplasia (Table 2) . All 19 adenomas with mild dysplasia retained the strong expression of Fhit displayed by normal mucosa; the higher grades of dysplasia showed weaker expression of Fhit (Table 2 ; Fig. 1, E and F ). A smaller proportion (6 of 36; 17%) of adenomas with moderate or severe dysplasia showed reduced expression of Fhit (² = 7.0691, df = 1, P = 0.0078) than that (44%) observed in carcinomas (Tables 1 and 2) .

	Discussion

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Alterations of the FHIT gene and/or its expression have also been reported in premalignant lesions of the lung (4) , esophagus (7) , and cervix (12) . Aberrant mRNA transcripts have been reported in premalignant lesions of the colon (18) . ACF are putative precancerous lesions that are identified microscopically in whole mounts of grossly normal colonic mucosa of humans (reviewed in Ref. 19 ). A variety of alterations have been identified in human ACF, including morphological changes from atypia to varying degrees of dysplasia (20) , histochemically detectable altered enzyme activities, increased proliferative activity, somatic APC and K-ras mutations, replication error phenotype, and the expression of antigens associated with malignancy (reviewed in Ref. 19 ). Most recently, human ACF have been demonstrated to be monoclonal lesions (21) . With only small proportions of both ACF and adenomas with reduced expression of Fhit, it might be hypothesized that Fhit does not play an important role very early in the tumorigenic process in the colon. Sozzi et al. (4) reported the reduction of Fhit expression in 93% of precancerous lesions of the lung, but their lesions in the lung appear much more advanced than ours in the colon. Their precancerous lesions included 25 carcinomas in situ and 20 dysplastic lesions; their only lesion with mild dysplasia, like our lesions with mild dysplasia, retained strong Fhit expression (4) . Similarly, Birrer et al. (12) found that a third of high-grade lesions but only 1 of 12 low-grade premalignant lesions in the cervix had altered Fhit expression. The strong association of Fhit expression with the degree of dysplasia in both ACF and adenomas suggests that Fhit may have a functional role in the early development of some colon tumors, as appears to be the case in the lung and cervix. The demonstration that there is no difference in Fhit expression between ACF with moderate and severe dysplasia and adenomas with moderate and severe dysplasia provides additional support for ACF as premalignant lesions of the colon.

The mechanisms leading to the reduction of Fhit expression and the manner in which FHIT promotes tumorigenesis remain obscure. Heterozygous and/or homozygous deletions of important exons from the FHIT gene may result in changes of protein expression. A good correlation has been reported for alterations of the FHIT gene with aberrant mRNA transcripts and/or reduction of Fhit protein expression (1 , 10) . In colorectal cancer, loss of heterozygosity of the FHIT gene has been reported in 16 of 33 informative colon cancers (13) , but protein expression was not analyzed. Missense, nonsense, or frameshift mutations in the FHIT gene appear to be rare in primary tumors (1) , e.g., a point mutation was reported in 1 of 40 gastric carcinomas (9) . Hypermethylation of a 5' CpG island appeared to silence the FHIT gene in some esophageal cancers (8) . The gene is composed of 10 exons and spans over one megabase of DNA (1) . Exons 5–9 encode a 16.8-KDa protein that hydrolyzes diadenosine 5',5'''-p1,p3-triphosphate (Ap3A) to ADP and AMP in vitro (1) . Both wild-type and mutant Fhit proteins that lack hydrolase activity were able to suppress tumorigenicity in athymic mice of cell lines that failed to express Fhit (22) . More recently, overexpression of the FHIT gene by adenovirus transduction of FHIT-defective human cancer lines inhibited cell growth and induced apoptosis in vitro and inhibited tumor cell growth in vivo (23) .

In summary, the expression of Fhit was markedly reduced or absent in a significant proportion of colorectal cancers and in an even higher proportion of metastatic lesions. Although the proportion of adenomas and ACF with reduced expression of Fhit was small, this reduced expression showed a strong association with dysplasia. These results suggest that FHIT plays a role in the development and progression of colorectal cancer from the premalignant stage through metastasis.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by USPHS Grants CA66725, CA54031, and CA43703 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106. Phone: (216) 368-8702; FAX: (216) 368-1278; E-mail: tpp3{at}po.cwru.edu

³ The abbreviations used are: ACF, aberrant crypt foci; FAP, familial adenomatous polyposis.

Received 11/ 9/99. Accepted 11/22/99.

	REFERENCES

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1. Huebner K., Druck T., Siprashvili Z., Croce C. M., Kovatich A., McCue P. A. The role of deletions at the FRA3B/FHIT locus in carcinogenesis. Recent Results Cancer Res., 154: 200-215, 1998.[Medline]
2. Ohta M., Inoue H., Cotticelli M. G., Kastury K., Baffa R., Palazzo J., Siprashvili Z., Mori M., McCue P., Druck T., Croce C. M., Huebner K. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell, 84: 587-597, 1996.[Medline]
3. Burke L., Khan M. A., Freedman A. N., Gemma A., Rusin M., Guinee D. G., Bennett W. P., Caporaso N. E., Fleming M. V., Travis W. D., Colby T. V., Trastek V., Pairolero P. C., Tazelaar H. D., Midthun D. E., Liotta L. A., Harris C. C. Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer. Cancer Res., 58: 2533-2536, 1998.[Abstract/Free Full Text]
4. Sozzi G., Pastorino U., Moiraghi L., Tagliabue E., Pezzella F., Ghirelli C., Tornielli S., Sard L., Huebner K., Pierotti M. A., Croce C. M., Pilotti S. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res., 58: 5032-5037, 1998.[Abstract/Free Full Text]
5. Campiglio M., Pekarsky Y., Menard S., Tagliabue E., Pilotti S., Croce C. M. FHIT loss of function in human primary breast cancer correlates with advanced stage of the disease. Cancer Res., 59: 3866-3869, 1999.[Abstract/Free Full Text]
6. Kisielewski A. E., Xiao G. H., Liu S. C., Klein-Szanto A. J. P., Novara M., Sina J., Bleicher K., Yeung R. S., Goodrow T. L. Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck. Oncogene, 17: 83-91, 1998.[Medline]
7. Michael D., Beer D. G., Wilke C. W., Miller D. E., Glover T. W. Frequent deletions of FHIT and FRA3B in Barrett’s metaplasia and esophageal adenocarcinomas. Oncogene, 15: 1653-1659, 1997.[Medline]
8. Tanaka H., Shimada Y., Harada H., Shinoda M., Hatooka S., Imamura M., Ishizaki K. Methylation of the 5' CpG island of the FHIT gene is closely associated with transcriptional inactivation in esophageal squamous cell carcinomas. Cancer Res., 58: 3429-3434, 1998.[Abstract/Free Full Text]
9. Gemma A., Hagiwara K., Ke Y., Burke L. M., Khan M. A., Nagashima M., Bennett W. P., Harris C. C. FHIT mutations in human primary gastric cancer. Cancer Res., 57: 1435-1437, 1997.[Abstract/Free Full Text]
10. Sorio C., Baron A., Orlandini S., Zamboni G., Pederzoli P., Huebner K., Scarpa A. The FHIT gene is expressed in pancreatic ductular cells and is altered in pancreatic cancers. Cancer Res., 59: 1308-1314, 1999.[Abstract/Free Full Text]
11. Xiao G. H., Jin F., Klein-Szanto A. J. P., Goodrow T. L., Linehan M. W., Yeung R. S. The FHIT gene product is highly expressed in the cytoplasm of renal tubular epithelium and is down-regulated in kidney cancers. Am. J. Pathol., 151: 1541-1547, 1997.[Abstract]
12. Birrer M. J., Hendricks D., Farley J., Sundborg M. J., Bonome T., Walts M. J., Geradts J. Abnormal Fhit expression in malignant and premalignant lesions of the cervix. Cancer Res., 59: 5270-5274, 1999.[Abstract/Free Full Text]
13. Kastury K., Baffa R., Druck T., Ohta M., Cotticelli M. G., Inoue H., Negrini M., Rugge M., Huang D., Croce C. M., Palazzo J., Huebner K. Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3B site identified by homozygous deletions in tumor cell lines. Cancer Res., 56: 978-983, 1996.[Abstract/Free Full Text]
14. Thiagalingam S., Lisitsyn N. A., Hamaguchi M., Wigler M. H., Willson J. K. V., Markowitz S. D., Leach F. S., Kinzler K. W., Vogelstein B. Evaluation of the FHIT gene in colorectal cancers. Cancer Res., 56: 2936-2939, 1996.[Abstract/Free Full Text]
15. Wingo P. A., Ries L. A., Giovino G. A., Miller D. S., Rosenberg H. M., Shopland D. R., Thun M. J., Edwards B. K. Annual report to the nation on the status of cancer, 1973–1996, with a special section on lung cancer and tobacco smoking. J. Natl. Cancer Inst., 91: 675-690, 1999.[Abstract/Free Full Text]
16. Hao X., Tomlinson I., IIyas M., Palazzo J. P., Talbot I. C. Reciprocity between membranous and nuclear expression of ß-catenin in colorectal tumours. Virchows Arch., 431: 167-172, 1997.[Medline]
17. Agresti, A. Models for binary response data. In: Categorical Data Analysis, pp. 79–129. New York: Wiley, 1990.
18. Luceri C., Hay K., Tjan S., Couture J., Gallinger S., Bapat B. Molecular analysis of the FHIT gene in colonic aberrant crypt foci and adenomas of familial adenomatous polyposis (FAP) patients. Proc. Am. Assoc. Cancer Res., 39: 619 1998.
19. Pretlow T. P., Siddiki B., Augenlicht L. H., Pretlow T. G., Kim Y. S. Aberrant crypt foci (ACF)—earliest recognized players or innocent bystanders in colon carcinogenesis Schmiegel W. Scholmerich J. eds. . Colorectal Cancer: Molecular Mechanisms, Premalignant State and Its Prevention, : 67-82, Kluwer Academic Publishers Hingham, MA 1999.
20. Siu I-M., Pretlow T. G., Amini S. B., Pretlow T. P. Identification of dysplasia in human colonic aberrant crypt foci. Am. J. Pathol., 150: 1805-1813, 1997.[Abstract]
21. Siu I-M., Robinson D. R., Schwartz S., Kung H-J., Pretlow T. G., Petersen R. B., Pretlow T. P. The identification of monoclonality in human aberrant crypt foci. Cancer Res., 59: 63-66, 1999.[Abstract/Free Full Text]
22. Siprashvili Z., Sozzi G., Barnes L. D., McCue P., Robinson A. K., Eryomin V., Sard L., Tagliabue E., Greco A., Fusetti L., Schwartz G., Pierotti M. A., Croce C. M., Huebner K. Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc. Natl. Acad. Sci. USA, 94: 13771-13776, 1997.[Abstract/Free Full Text]
23. Ji L., Fang B., Yen N., Fong K., Minna J. D., Roth J. A. Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. Cancer Res., 59: 3333-3339, 1999.[Abstract/Free Full Text]

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