[雙語翻譯]---醫(yī)學(xué)外文翻譯--青年胃癌患者的微衛(wèi)星不穩(wěn)定性和或雜和性缺失（原文）

1、MICROSATELLITE INSTABILITY AND/OR LOSS OF HETEROZYGOSITY IN YOUNG GASTRIC CANCER PATIENTS IN ITALYYih-Horng SHIAO1, Daniela BOVO2, Maria GUIDO2, Carlo CAPELLA3, Mauro CASSARO2, Graziella BUSATTO2, Valentina RUSSO2,4, Ang

2、elo SIDONI5, Anna R. PARENTI2 and Massimo RUGGE2*1Laboratory of Comparative Carcinogenesis, NCI-FCRDC, National Institutes of Health, Frederick, MD, USA 2Department of Oncological and Surgical Sciences, Cattedra di Istoc

3、himica e Immunohistochimica Patologica, III Cattedra di Anatomia Patologica, Universita ´ Degli Studi, Padova, Italy 3Department of Clinical and Biological Science, University of Pavia, Varese, Italy 4Department of

4、Pathology, University of Catania, Catania, Italy 5Department of Pathology, University of Perugia, Perugia, ItalyGastric cancers are rarely diagnosed before the age of 40 years and the incidence reaches a peak during the

5、7th decade in the general population. A molecular mechanism of early tumor onset may be determined by comparing microsatellite instability (MSI), indicative of error-prone mismatch repair, and loss of heterozygosity (LOH

6、) between gastric cancers in patients I40 years of age and those of older ages. Three to 5 chromosomal loci, where MSI and/or LOH are commonly found in gastric cancers in the general population, were examined in formalin

7、-fixed, paraffin-embedded samples from 102 patients I40 years of age using a polymerase chain reaction-based non-radioactive screening method. MSI and/or LOH at a minimum of 1 locus were detected in 11/102 patients. The

8、frequency of MSI and/or LOH at the D11S904 locus was significantly higher than that at the D2S119, D2S123, D5S409 and IFNA regions. No preferential genetic changes at the D11S904 locus were observed in elderly patients.

9、Among several clinicopathological variables, a statis- tically significant association with MSI and/or LOH was ob- served only for tumors located at the cardia, compared with tumors at the antrum and the corpus. Our find

10、ings suggest that a unique mechanism may be involved in increasing the susceptibility of the D11S904 locus for either MSI or LOH, especially for cardia tumors in young patients. Early onset of gastric cancers in patients

11、 I40 years of age is associated with genetic changes at preferential chromosomal loci, including D11S904. Int. J. Cancer 82:59–62, 1999. ? 1999 Wiley-Liss, Inc.Although gastric cancer incidence has been declining, it was

12、 still ranked as the 2nd most common cancer and the 2nd leading cause of cancer death in the world in the 1990s (Parkin et al., 1993). Because of the aggressive nature of gastric cancers, the overall 5-year survival rate

13、 is less than 20% (Breaux et al., 1990). Gastric cancers usually occur in patients older than 50 years of age; only about 5% of gastric cancer patients are younger than 40 years (Neugut et al., 1996). Gastric cancers in

14、patients ?40 years of age are more aggressive than those in elderly patients (Fujimoto et al., 1994). Comparison of genetic alterations in gastric cancers be- tween patients ?40 years of age and older patients may identi

15、fy a specific molecular mechanism associated with an early onset of tumor. Microsatellites are short tandemly repeated DNA sequences and present throughout mammalian genomes. Repetitive sequences of di-, tri- and tetranu

16、cleotide repeats are present in more than 50% of the human genome (Beckman and Weber, 1992). The tandem repeats of (dC-dA)n are particularly abundant. Alterations in the number of repeats per site, known as microsatellit

17、e instability (MSI), have been implicated in various human diseases, including neoplasms (Speicher, 1995). Microsatellite sequences are also highly polymorphic. Polymorphism due to different number of repeats is very use

18、ful to determine genetic alterations, such as loss of heterozygosity (LOH). In this study, we examined 5 chromosomal loci, where MSI and/or LOH are commonly found in gastric cancers in the generalpopulation (Rhyu et al.,

19、 1994; Chong et al., 1994; Nagel et al., 1995; Tamura et al., 1995; Lin et al., 1995; Seruca et al., 1995; Buonsanti et al., 1997), in gastric cancer patients ?40 years of age. The frequency of MSI and/or LOH and their a

20、ssociation with other clinicopathological data are discussed.MATERIAL AND METHODS PatientsFormalin-fixed, paraffin-embedded tissue blocks from 102 pa- tients ?40 years of age (mean age: 35 years; range: 16–40 years) were

21、 retrieved from the archives of many Italian hospitals with comparable gastric cancer incidence. Demographic and pathologi- cal data, including age, gender, site of tumor and tumor stage using the TNM system (Beahrs and

22、Myers, 1983), were obtained from a collaborative multicenter study. The site of tumor was categorized into the antrum, corpus or cardia of stomach. No cancer extended beyond the gastric-esophageal junction. According to

23、the Laure ´n system (1965), gastric cancers were classified as either intestinal or diffuse type. When both phenotypes coexisted, classification of the tumor type was based on the most representative histology. Gast

24、ritis (non-atrophic vs. atrophic/metaplastic) was classified using the Houston-updated Sydney System (Dixon et al., 1996).All cases were jointly assessed by 2 authors (M.C. and M.R.).DNA extraction Neoplastic and adjacen

25、t non-neoplastic areas were microdis- sected separately from unstained formalin-fixed, paraffin-embed- dedsections for deparaffinization, proteinase K digestion and DNA purification, as described previously (Shiao et al.

26、, 1994). Micro- dissected neoplastic areas contained at least 50% tumor cells. When possible, lymphocytes were used as a non-neoplastic cell control.Polymerase chain reaction (PCR) Five chromosomal loci with (CA)n dinucl

27、eotide repeats (D2S119, D2S123, D5S409, IFNA and D11S904) were selected for PCR. Primers (D2S123: AFM093xh3a and AFM093xh3m; D5S409: AFM184yb6a and AFM184yb6m; IFNA: IFNA.PCR2.1 and IFNA.PCR2.2; D11S904: AFM081za5a and A

28、FM081za5m) were obtained from the Genome Database web site (www.gdb.org). For D2S119, upper (5?-CCAGTTTGGAAGCATTTTCA-3?) and lowerD. Bovo is now at Department of Pediatrics, University of Padova, Padova, Italy.*Correspon

29、dence to: Department of Oncological and Surgical Sciences, University of Padova, Via Aristide Gabelli, 61, I-35121 Padova, Italy. Fax: (39)049-942-4981. E-mail: rugge@uxl.unipd.itReceived 5 January 1999; RevisedInt. J. C

30、ancer: 82, 59–62 (1999) ? 1999 Wiley-Liss, Inc.Publication of the International Union Against CancerPublication de l’Union Internationale Contre le Cancerdirect evidence of the contributory effect to tumor biology of the

31、 genetic changes at these loci. In our study, a significant association of MSI and/or LOH with tumors at the cardia suggests that a specific etiology is involved inthe induction of genetic changes at this anatomic site i

32、n young patients.Asimilar finding also has been reported in a small series of gastric cancers in elderly patients from Taiwan (Lin et al., 1995). However, these observations are different from other series of gastric can

33、cers in elderly patients from other geographic areas (Seruca et al., 1995; Gleeson et al., 1996). Further study is required to clarify the mechanism of genetic changes at different anatomic sites. A trend toward positive

34、, but not significant, association of MSI and/or LOH with male gender and Laure ´n intestinal-type gastric cancers is possibly a result of few chromosomal loci examined and/or low frequency of the genetic changes in

35、 these young patients. Increasing the number of chromosomal loci for examination is necessary to confirm the relationships between MSI and/or LOH alterations and clinicopathological data in gastric cancer patients ?40 ye

36、ars of age.In summary, a unique mechanism may be involved in increasing the susceptibility of the D11S904 locus for either MSI or LOH, especially for gastric cancers of the cardia in young patients. Early onset of gastri

37、c cancers in patients ?40 years of age is associated with genetic changes at preferential chromosomal loci, including the D11S904.ACKNOWLEDGEMENTSWe thank Drs. G. Beltrami (Udine, Italy), A. Fabiano (Roma, Italy) and E.

38、Edgarter-Vigl (Bolzano, Italy) for providing some of the tumor material.REFERENCESBEAHRS, O.H. and MYERS, M.H., American Joint Committee on Cancer. Manual for staging of cancer, pp. 127–130, Lippincott, Philadelphia (198

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48、., LEE, W.-J., WANG, J.-T., WANG, T.-H. and SHEU, J.-C., Microsatellite instability in gastric carcinoma with special references to histopathology and cancer stages. Europ. J. Cancer, 31A, 1879–1882 (1995).TABLE II – COM

49、PARISON OF THE FREQUENCY OF MSI AND/OR LOH BETWEEN YOUNG (THIS STUDY) AND ELDERLY PATIENTSReference D2S119 D2S123 D5S409 IFNA D11S904This study 1/96 (1%) 0/87 (0%) 2/99 (2%) 1/101 (1%) 9/100 (9%) Rhyu et al. (1994) 11/52

50、 (21%) 15/52 (29%) ND ND 9/52 (17%) Chong et al. (1994) ND1 17/75 (23%) ND ND ND Nagel et al. (1995) ND 7/19 (37%) ND ND ND Tamura et al. (1995) ND 3/23 (13%) 7/23 (30%) 6/23 (26%) ND Lin et al. (1995) ND 16/59 (27%) ND

51、ND ND Seruca et al. (1995) ND ND ND ND 4/24 (17%) Buonsanti et al. (1997) ND ND ND ND 2/8 (25%)1ND, not determined.TABLE III – FREQUENCY TABLE OF MSI AND/OR LOHVariables MSI and/or LOH OR1 p2 ? ?Age (years) 37–40 45 5 1.

52、0 1.00 ?36 46 6 1.2 Gender Female 51 4 1.0 0.34 Male 40 7 2.2 Laure ´n type Diffuse 65 6 1.0 0.30 Intestinal 26 5 2.1 Tumor site Antrum 57 5 1.0 ?0.01 Corpus 25 1 0.5 Cardia 9 5 6.3 Gastritis Non-atrophic 59 7 1.0 1