Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) seems to be closely associated with lung carcinogenesis. To identify the genetic characteristics of precancerous IPF lesions in the peripheral lung, we performed PCR-based microsatellite analysis with DNA extracted from microdissected tissues; fluorescent in situ hybridization (FISH) analysis of the fragile histidine triad (FHIT) gene and immunohistochemical analysis of Fhit protein expression in samples of metaplasias and bronchiolar epithelia obtained from patients with IPF. We used four microsatellite markers of the FHIT gene within or flanking the FHIT gene on chromosome 3p for loss of heterozygosity (LOH) analysis. LOH of the FHIT locus was frequently found among the lesions of metaplasias and bronchiolar epithelia in the patients with IPF [62 (52%) of 119 informative lesions]. Fifty-four (73%) of the 74 lesions of metaplasias and bronchiolar epithelia obtained from the IPF patients with lung carcinoma and 8 (17%) of the 46 samples obtained from the IPF patients without lung carcinoma showed LOH at the FHIT gene (P < 0.0001). We confirmed allelic loss in the metaplasias and bronchiolar epithelia of IPF by FISH analysis of the FHIT gene. Additionally, the level of Fhit protein expression in the metaplastic cells of IPF was frequently reduced. Our findings suggest that allelic loss of the FHIT gene may be involved in carcinogenesis in the peripheral lung of patients with IPF.     

人非小细胞肺癌中FHIT等位基因缺失和突变的研究

目的　探讨FHIT等位基因缺失、突变在肺癌发生、发展中的作用。方法　应用PCR SSCP和DNA序列分析方法对 3 5例人非小细胞肺癌和 4个肺癌细胞株中FHIT基因的 4个外显子 (外显子 3、4、5、8)和微卫星D3S13 0 0、D3S13 12、D3S13 13进行研究 ,并以远癌肺组织和 10例肺良性病变组织做对照。结果　在 3 5例肺癌中 ,2 2例肺癌发生了一个或两个以上的FHIT等位基因缺失 ,缺失率为 62 .86% ( 2 2 /3 5 )。在鳞癌中 ,FHIT等位基因缺失率 ( 88.2 4% ,15 /17)明显高于腺癌 ( 3 8.89% ,7/18) (P <0 .0 1) ;在吸烟患者中 ( 76.19% ,16/2 1)亦明显高于不吸烟患者 ( 4 2 .86% ,6/14 ) (P <0 .0 5 )。而FHIT等位基因缺失与肺癌的细胞分化程度、P TNM分期、原发肿瘤大小、部位、患者性别、年龄及有无转移均无明显关系 (P >0 .0 5 )。Lewis肺癌、A5 49细胞株亦有FHIT基因部分缺失。 4例肺癌组织具有微卫星灶D3S13 12点突变 ,经DNA序列分析显示均为D3S13 12微卫星灶基因的 87位点密码子发生了CT点突变。结论　FHIT基因异常主要以等位基因的缺失为主 ,而点突变发生率较低。FHIT等位基因缺失主要发生在肺鳞癌和吸烟患者中 ,且FHIT基因可能为烟草致肺癌的靶基因 ,其等位基因缺失可能是肺癌的早期分子事件。     

FHIT gene and flanking region on chromosome 3p are subjected to extensive allelic loss in Egyptian breast cancer patients

The fragile histidine triad gene (FHIT) is a candidate tumor suppressor gene at chromosome 3p14.2. Deletions in FHIT gene were reported in different types of cancer including breast cancer. In this study, we investigated the loss of heterozygosity (LOH) incidence that target FHIT genomic structure and chromosome 3p in cancerous and pre-neoplastic lesions of Egyptian breast patients. Genomic DNA was isolated from tumor tissues and their normal counterparts of 55 Egyptian patients diagnosed with breast cancer and 11 patients diagnosed with preneoplastic breast lesions. LOH was detected in 51% of breast cancer cases in at least one microsatellite marker of the four investigated markers. While, none of the markers showed LOH among the pre-neoplastic breast lesions. We also observed a significant association between LOH and invasive ductal carcinoma (IDC) histopathological type while no association observed between LOH and patients' age, tumor grade, or lymph node involvement. We also investigated FHIT gene expression profiles in breast cancer using Oncomine database. We found that FHIT is significantly reduced in all investigated studies. We conclude that, FHIT is underexpressed in breast cancer tissues compared to their normal counterparts due to the extensive allelic loss that is observed in its gene structure.     

Frequent FHIT gene loss of heterozygosity in human papillomavirus-infected non-smoking female lung cancer in Taiwan

The fragile histidine triad (FHIT), located in chromosome region 3p14.2, had been reported to be a frequent allele with loss of heterozygosity (LOH) in smoking lung cancer and HPV-associated cervical cancer. Additionally, FHIT LOH may act as a tumor suppressor gene to involve in smoking-related lung tumorigenesis and HPV-related cervical tumorigenesis, respectively. In our previous report, a high prevalence of HPV 16/18 infection has been observed in non-smoking female lung cancer patients, and thus it was speculated that HPV 16/18 infection may increase the LOH frequency of FHIT in female cases to implicate in lung tumorigenesis. In this study, 157 lung cancer patients were enrolled and subjected to FHIT LOH analysis with three microsatellite markers. As expected, the frequency of FHIT LOH in males, smokers, and squamous cell carcinomas lung cancer patients was significantly higher than that of their corresponding counterpart (P=0.020 for gender, P<0.001 for smoking status, and P=0.038 for tumor type). Interestingly, a correlation between HPV 16 infection and FHIT LOH was observed in female lung cancer cases. To be more specifically, FHIT LOH frequency was remarkably increased from 18% (6 of 33) in HPV 16 non-infected female cases to 46% (11 of 24) in HPV 16 infected cases. The higher frequency of FHIT LOH observed in HPV 16-infected female lung tumors suggested that the involvement of HPV infection in lung tumorigenesis may, at least in part, be mediated through FHIT LOH.     

p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with nonsmall cell lung carcinoma

BACKGROUND: An accumulation of mutations can result in carcinogenesis. Comparing genetic alterations in preneoplastic lesions with those seen in cancer in the same patient may be helpful in the early diagnosis of lung carcinoma or preneoplastic lesions. METHODS: To identify genetic alterations that may play a role in the development of nonsmall cell lung carcinoma (NSCLC), the authors examined the p53 gene and microsatellite markers on chromosome 3p (D3S643, D3S1317), 9p (D9S171, IFNA) in 35 bronchial metaplastic lesions and 28 alveolar hyperplastic lesions from 61 patients. RESULTS: A total of 8 metaplastic lesions (1 squamous metaplasia and 7 dysplasias) and 3 alveolar hyperplastic lesions (with atypia) showed genetic alterations, including loss of heterozygosity (LOH) of 3p, 9p and mutations of the p53 gene. In an analysis of microsatellite markers, 5 of 35 cases of squamous cell carcinoma (SCC) and 3 of 26 cases of adenocarcinoma (Ad) showed LOH in both preneoplastic lesions and synchronous cancers. Nine patients (25.7%) with SCC and 6 patients (23.1%) with Ad were shown to have mutations of the p53 gene by single-strand conformation polymorphism. In 2 of these 9 patients with SCC, the same mutation was observed in both dysplasia and SCC. CONCLUSIONS: These findings suggest that several genetic alterations may occur in preneoplastic lesions or the early stage of SCC of the lung, whereas the genetic alterations examined appeared to occur relatively late in the pathogenesis of pulmonary adenocarcinoma.     

非小细胞肺癌中脆性组氨酸三联体基因异常的探讨

目的:探讨脆性组氨酸三联体(FHIT)基因在非小细胞肺癌(NSCLC)中作用机制及其与临床病理间的关系。方法:通过PCR-变性聚丙烯酰胺凝胶电泳-硝酸银染色方法检测40例非小细胞肺癌及其癌旁肺组织与FHIT基因紧密连锁的D3S1300位点杂合性缺失(LOH),并比较其与各临床病理的关系。结果:1)FHIT基因在肺癌组和对照组杂合性缺失的发生率分别为70.0%和0,两组比较有显著性差异(P<0.001)。2)发生FHIT基因杂合性缺失的28例肺鳞癌患者中23例(82.1%)有吸烟史;发生FHIT基因杂合性缺失的12例肺腺癌患者中7例(58.3%)有吸烟史。FHIT基因杂合性缺失与吸烟因素及肺癌组织类型具有相关性(P<0.05)。3)FHIT基因杂合性缺失的发生率与年龄、性别、临床分期、淋巴结转移等临床病理间无明显相关性。结论:非小细胞肺癌FHIT基因杂合性缺失与吸烟因素密切相关,提示FHIT基因可能是烟中致癌物的靶分子。     

肺癌前病变、肺癌中FHIT基因表达的临床研究

背景与目的FHIT基因为近年发现的新的候选抑癌基因，位于3p14．2，跨越FRA3B易脆点，在包括肺癌在内的多种人类肿瘤中均存在异常表达。本研究旨在观察FHIT基因在人肺癌前病变、肺癌中的表达情况，探讨FHIT基因在肺癌发生、发展过程中的可能作用。方法采用免疫组化方法检测298例甲醛固定、石蜡包埋的标本（包括161例肺癌、51例肺癌前病变、30例正常肺组织、23例肺良性病变和33例肺癌转移淋巴结）中FHIT蛋白表达情况。结果FHIT蛋白在正常肺组织及肺良性病变组织中均无失表达，癌前病变组织和肺癌组织中失表达率分别为54．9％（28／51）和59．0％（95／161），肺癌转移淋巴结组织中失表达率为78．8％（26／33）；肺癌前病变、肺癌及转移淋巴结组织中FHIT蛋白失表达率显著高于正常肺组织及肺良性病变组织（P〈0．001）。肺癌组织中FHIT基因表达水平与肺癌组织学类型、肿瘤细胞分化程度、患者pTNM分期、淋巴结转移有密切关系（P〈O．05）。FHIT蛋白失表达组肺癌患者的术后5年生存率显著低于表达组（P〈0．01）。吸烟组患者FHIT基因失表达率69．1％显著高于无吸烟组49．5％（P〈0．01）。结论FHIT蛋白失表达可能是肺癌发生过程中的早期分子事件，与肺癌的发生、发展及预后有关；吸烟导致FHIT蛋白表达下降可能是诱发肺癌的原因之一。     

膀胱移行细胞癌中FHIT基因杂合性缺失及其蛋白表达的研究

目的分析候选抑癌基因FHIT及其蛋白表达在中国人膀胱移行细胞癌(transitional cell carcinoma,TCC)中的异常改变,探讨其潜在的临床意义.方法选取两个位于FHIT基因第5内含子的微卫星多态标记,对40例膀胱TCC患者的肿瘤组织和尿沉渣DNA进行杂合性缺失(loss of heterozygosity,LOH)分析,同时对相应的组织病理切片进行FHIT蛋白的免疫组化染色.结果在40例膀胱TCC患者的肿瘤组织中,两个微卫星多态标记D3S1234和D3S1300中至少有一个发生LOH的频率为57.8%;而在相应的尿沉渣DNA中,这两个位点中至少有一个发生LOH的频率为55.8%.同时在62.5%(25/40)的膀胱TCC肿瘤组织检出FHIT蛋白表达缺失;而在FHIT蛋白表达缺失的25例肿瘤组织中,有20例存在一个或两个上述微卫星位点的LOH.结论 FHIT基因在膀胱TCC患者的肿瘤组织和尿沉渣DNA中存在高频率LOH,提示这一基因在膀胱TCC的发生发展中可能起重要作用;杂合性缺失可能是膀胱TCC中FHIT蛋白表达下调的重要机理之一.而尿沉渣DNA中FHIT基因的LOH则有可能成为膀胱TCC早期诊断的潜在分子标志之一.     

FHIT基因与喉癌相关性的研究

目的 研究ＦＨＩＴ基因在喉癌发生中的作用。方法 应用ＲＴ－ＰＣＲ技术筛查了喉细胞系Ｈｅｐ－２，宫颈癌细胞系ＨｅＬａ和２０例原发性喉癌的ＦＨＩＴ基因转录本，对其中的２例异常转录本进行了测序分析。同时，对另外６０例原发性喉癌ＦＨＩＴ基因进行了微卫星多态分析。结果 在２０例喉癌中，１４例，显示ＦＨＩＴ基因异常转录本，Ｈｅｐ－２和ＨｅＬａ细胞系ＦＨＴ基因转录本均存在缺失。     

Mycobacterium tuberculosis infection and FHIT gene alterations in lung cancer

Although it is fairly well accepted that pulmonary tuberculosis is a major risk factor of lung cancer, the exact molecular mechanisms involved in its tumorigenesis are unclear. For this purpose, we have examined the relationship between Mycobacterium tuberculosis (M-TB) infection and FHIT gene alteration in lung cancer. Tumors with M-TB infection had a slightly higher abnormal FHIT protein expression compared with tumors without M-TB infection, although not statistically significant (Fisher's exact test, P=0.248). LOH affecting at least one locus of the FHIT gene was significantly more frequent in lung cancer patients with M-TB infection than in patients without M-TB infection whether assessment by univariate testing methods or logistic regression modeling analysis (Fisher's exact test P=0.025, logistic regression analysis P=0.012). These results indicate that M-TB infection is associated with FHIT gene LOH in lung cancer.     

肺癌中ING1基因变化及其表达水平的研究

目的：检测肺癌中抑癌基因ING1微卫星杂合性缺失（LOH）及其主要蛋白产物p33^ING1b的表达情况，以探讨ING1基因改变-9肺癌发生发展的关系。方法：采用银染PCR—SSCP法检测肺癌组织ING1基因微卫星LOH发生的频率；应用组织芯片技术和免疫组化方法，检测肺癌p33^ING1b蛋白表达水平。结果：70例肺癌组织ING1基因4个微卫星位点的总杂合性缺失率为55．7％（39／70），并且越靠近ING1基因位点，发生率越高，但与临床病理参数无关。217例肺癌p33^ING1b蛋白的LOH发生率为47．0％（102／217），鳞状细胞癌高于腺癌、腺鳞癌和细支气管肺泡癌（P〈0．05），其余类型间差异无显著性（P〉0．05）；p33^ING1b的表达与其他临床病理参数不相关（P〉0．05），但与LOH发生频率相关（P〈0．05）。结论：p33^ING1b蛋白在肺癌组织中存在高频率的低表达或失表达，并且ING1基因的微卫星LOH发生频率也很高。推测LOH是该基因异常表达的重要原因，其结果可能导致该基因的下调和（或）蛋白质功能的失活，从而丧失其对细胞的生长抑制作用，促进了肿瘤的发生。     

河南食管癌高发区居民食管癌变过程中微卫星LOH的特征

目的微卫星（microsatellite）是广泛分布于生物基因组中的DNA重复序列，与许多重要基因紧密连锁。本研究旨在探讨食管癌变多阶段演进过程中微卫星DNA杂合缺失（loss of heterozygosity，LOH）的特征及其意义。方法采用微卫星DNA多态分析法，选取染色体3p、5q、6p、9p、13q、17p、17q和18q的15个多态微卫星位点，对32例食管癌前病变和癌组织进行LOH分析。结果食管各级癌前病变组织和癌组织均出现不同程度的微卫星DNALOH，其频率随病变程度加重而明显升高（除D9S1752位点外，P均〈0．05）；其中D9S171、D13S260和TP53位点在癌阶段，LOH频率均超过60％。各级癌前病变组织和癌组织中发生LOH的位点不尽相同，同一个体从基底细胞过度增生→间变→原位癌→鳞状细胞癌，均发生LOH的位点是：D3S1234和TP53。结论基因水平的改变发生在食管癌变的早期阶段，随病变程度加重，基因组不稳定性增强，可能是导致食管癌前病变持续向癌的方向发展的重要机制之一。     

应用组织芯片研究肺癌及癌前病变组织中FHIT的表达及其意义

背景与目的 脆性组氨酸三联体(fragile histidine triad,FHIT)是候选抑癌基因,在多种与环境致癌物有关的恶性肿瘤中常有FHIT的改变.本研究利用组织芯片技术检测FHIT在不同进展阶段肺癌中的表达,探讨其在肺癌发生、发展中的作用和意义.方法 应用免疫组织化学SP法检测270点组织芯片中FHIT蛋白的表达,其中原发肺癌89例、淋巴结转移性肺癌12例以及肺癌癌前病变12例,并结合肺癌的临床病理特征进行分析.结果 FHIT蛋白阳性产物主要定位于胞浆.在原发性肺癌、癌前病变组织和淋巴结转移癌组织中FHIT表达缺失率分别为46.1%、41.7%和50.0%,而在10例正常肺组织中FHIT均有表达.原发性肺癌组、癌前病变组和转移癌组FHIT蛋白的表达缺失率均高于正常组(P＜0.05);原发癌与转移癌、原发癌与癌前病变、癌前病变与转移癌之间FHIT表达差别无统计学意义(P＞0.05),且FHIT表达缺失与肺癌组织学类型、分化程度以及患者的吸烟史相关且有统计学意义(P＜0.05),而与性别、年龄、临床分期、是否伴有淋巴结转移以及肉眼类型无关(P＞0.05).结论 FHIT在肺癌和癌前病变中表达下降,尤其在鳞癌、低分化组和吸烟病例中表达缺失率高,FHIT表达缺失可能与肺癌早期发生、发展及吸烟致癌过程有密切的关系.     

Analysis of the fragile histidine triad (FHIT) gene in lobular breast cancer

The fragile histidine triad (FHIT) gene is a candidate tumour suppressor gene in breast and other cancers. We investigated deletions within the FHIT gene in lobular breast cancer and found that 16% of cases showed loss of heterozygosity (LOH) within the gene. We compared LOH within FHIT in lobular and ductal breast tumours and found a significant association between LOH at FHIT and the ductal histological type (P<0.001). To determine whether genomic alteration of the FHIT gene in lobular breast cancer leads to Fhit inactivation we have assessed the level of Fhit expression by immunohistochemical detection and determined that 27% (15 of 55) consecutive sporadic lobular tumours showed negative or reduced Fhit expression. A significant association was found between LOH at the FHIT gene and reduced Fhit expression in lobular and ductal tumours (P=0.025 and P=0.001, respectively). Thus, genetic alterations within the FHIT gene, leading to loss of Fhit protein, may play an important role in the carcinogenesis of a significant number of sporadic lobular breast cancers, even though the apparent frequency of genomic alterations within the gene is lower than in ductal breast cancer.     

Loss of heterozygosity and microsatellite instability in epithelial hyperplasia of the breast

We evaluated loss of heterozygosity (LOH) and microsatellite instability (MSI) in epithelial hyperplasia of the breast by the PCR method using microsatellite markers. Seven loci of 16q, 17p, 17q, and 18q were examined in 35 lesions of epithelial hyperplasia observed in non-neoplastic breast tissue of eight breast carcinoma cases, and 29 lesions were observed within 19 fibroadenomas. These hyperplastic lesions were classified by standard criteria into three groups, namely, mild, moderate and atypical ductal hyperplasia (ADH). In the breast carcinoma cases, the frequency of loss of heterozygosity was 40% in mild, 50% in moderate, and 100% in ADH; while in the fibroadenoma cases, the frequency was 10% in mild, 27% in moderate, and 25% in ADH; total frequency of LOH was statistically higher in carcinoma cases than in fibroadenoma cases. On the other hand, the frequency of microsatellite instability was higher in fibroadenoma cases (28%) than in breast carcinoma cases (11%). Furthermore, we analyzed two cases of noninvasive ductal carcinoma arising in fibroadenoma, which had various types of hyperplasia along with carcinoma in situ, and many hyperplasias showed LOH at several of the same markers as carcinoma in situ. From those results, we speculated that LOH at these markers is an early event in mammary tumorigenesis, and some of the hyperplastic lesions with LOH have precancerous natures.     

Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer

Papilloma and papillary hyperplasia (PH) have been proposed to be the putative precursor lesions of papillary transitional-cell carcinoma of the urinary bladder. We examined 15 PH lesions and 4 papillomas for loss of heterozygosity (LOH) at 17 microsatellite markers on 9 chromosomal arms. Eight of 15 (53%) PHs were clonal, demonstrating LOH of at least 1 microsatellite marker. In contrast, none of the papillomas showed any genetic changes among the markers tested. In PH, chromosomal arm 9q was the most frequently lost (4/15), followed by 9p and 18q (n = 2) and, less frequently, 8p, 10q, 11p and 17p (n = 1). Furthermore, 2 hyperplastic lesions demonstrated LOH at 9q only, confirming the notion that allelic loss on chromosomal arm 9q is among the earliest events in bladder-cancer progression. In 1 patient, identical LOH patterns were observed between PH and a recurrent transitional-cell carcinoma. Our molecular data demonstrate that at least a proportion of PHs represent pre-cancerous lesions of the bladder that subsequently progress to papillary bladder cancer. Moreover, chromosomal arm 9q may harbor a tumor-suppressor gene(s) inactivated in the earliest stages of human bladder tumorigenesis.     

Alterations of the FHIT gene in breast cancer: association with tumor progression and patient survival.

Our previous results on breast tumors show that LOH (loss of heterozygosity) at the FHIT locus is associated with reduced Fhit protein expression. We have also shown that LOH at this locus is significantly higher in tumors from patients carrying the BRCA2 999de15 mutation than in tumors without this mutation, presumably because of lack of DNA repair. Here, our aim was to determine the relationship of FHIT LOH with breast tumor progression. Five microsatellite markers located within the FHIT gene were typed in 239 breast tumors and corresponding normal tissue, and the LOH results were compared with clinicopathologic factors and LOH at other chromosome regions. LOH at FHIT is associated with estrogen- and progesterone-negative breast tumors, high S-phase fraction, reduced patient survival, and LOH at chromosome regions 6q, 7q, 8p, 9p, 11p, 11q, 13q, 16q, 17p, 17q, 18q, and 20q. A multivariate analysis shows that LOH at FHIT results in a 60% increased relative risk of dying. We conclude that the loss of FHIT results in growth advantage of breast tumor cells, is associated with unstable genome, and may be of prognostic value.     

肺癌组织和转移性肺门淋巴结中FHIT基因和p16基因的变化

目的 研究肺癌组织和转移性肺门淋巴结中组氨酸三联体基因和Ｐ１６基因的突变方法 采用ＲＴ－ＰＣＲ和ＲＴ－ＰＣＲ－ＳＳＣＰ方法对４９例肺 １６例相应的转移性肺门淋巴结进行Ｐ１６基因和ＦＨＩＴ基因检测,其中２例肺癌组织仅行Ｐ１６基因检测。结果 ３２例（６８．１％）肺癌原发灶（包括２例肺鳞状细胞原位癌）和１５例（９３．８％）转移性肺门淋巴结出现ＦＨＩＴ转录本缺失,二者失率相比,差异有显著性。ＦＨＩＴ基因转     

乳腺癌与癌前病变的微卫星不稳定性与3p杂合性缺失

目的探讨微卫星不稳定性(MSI)与3号染色体短臂杂合性缺失(LOH)在乳腺癌发生机制中的作用及其临床病理学意义。方法采用PCR-SSLP及银染方法检测41例乳腺癌和13例癌前病变中MSI状态以及3p上11个微卫星位点LOH发生情况;应用免疫组化SP法检测错配修复(MMR)基因hMLH1、hMSH2和3p上相关基因的表达情况。结果(1)乳腺癌MSI发生率为36.6%,低分化乳腺癌MSI发生率明显高于高中分化组;癌前病变的发生率为15.4%;良性增生均表现微卫星稳定。(2)乳腺癌中微卫星异常主要分布于D3S1766、D2S2739和TP53 3个位点,癌前病变和乳腺癌具有相同的高频不稳定位点D3S1766和D2S2739。(3)97.0%乳腺癌患者发生3p LOH,检出率较高的位点分别是D3S1295、D3S1029和D3S1038。癌前病变患者3p LOH发生率为41.7%,缺失率较高的位点是D3S1295和D3S1029。(4)hMLH1和hMSH2蛋白在乳腺癌中阳性表达率分别为45.0%和40.0%,在癌前病变中分别为61.5%和76.9%,均明显低于良性增生组(P<0.05)。乳腺癌中两种蛋白阳性率与组织学分级相关(P<0.05),高分化组明显高于低中分化组。MSI 乳腺癌和癌前病变均表现MMR蛋白表达缺失。结论错配修复基因表达缺陷和MSI是乳腺癌多步骤发展过程的早期事件,在进展阶段MSI与乳腺癌低分化相关;D3S1766和D2S2739可能是检测乳腺癌与癌前病变MSI较敏感的位点。3p最小共同缺失区位于3p14-p25,提示该区域有与乳腺肿瘤发生发展相关并影响其生物学行为的候选抑癌基因。