p53 protein accumulation and mutations in normal and benign breast tissue

Mutations in the p53 gene are amongst the most common molecular changes detected in breast cancer, and there are several reports suggesting that changes in p53 may contribute to the pathogenesis of this disease. In a previous case-control study, we demonstrated that p53 protein accumulation detected by immunohistochemistry in normal or benign breast tissue was associated with a 2.5-fold increase in the risk of subsequent breast cancer. In this study, we investigated whether p53 gene mutations were present in the 29 p53 immunopositive normal or benign breast tissue samples and in 15 p53 immunonegative normal or benign breast tissue samples selected randomly from the original study. DNA was extracted from paraffin sections and underwent PCR-SSCP analysis for exons 4 to 10. PCR products that showed abnormal mobility were excised and sequenced. Sixteen (59.2%) of the 27 immunopositive breast tissue samples and 4 (26.7%) of the 15 immunonegative samples had p53 sequence changes. There was no obvious association between the occurrence of these alterations and any specific histopathologic features. Ten cases showed p53 mutations, and they were all missense base substitutions of the transition type. Thirteen other gene changes occurred in 11 breast tissue samples and consisted of 8 silent (no amino acid change), 4 intronic alterations, and 1 indeterminate alteration. One individual had both a mutation and a silent change. In summary, p53 gene alterations can occur in normal or benign breast tissue, but resolution of their role in the pathogenesis of breast cancer will require long-term follow-up studies involving comparisons of breast cancer occurrence in patients with and without p53 mutations as well as functional assays to determine their significance.     

乳腺良恶性病变GSTP1 基因的突变和多态性分析*

目的:检测谷胱甘肽S-转移酶P1（glutathione S-transferase P 1，GSTP1）基因各外显子的突变和多态性，探讨其与乳腺癌发生的关系。方法:选取乳腺癌及其相应癌旁增生组织标本各50例，良性增生组织标本50例，正常乳腺组织50例和正常人（志愿者）血液淋巴细胞15例为研究对象，运用PCR-SSCP 技术和DNA测序的方法检测GSTP1 基因外显子突变和多态性。结果:1）在3/50例（6%）乳腺癌组织中检测到GSTP1 基因外显子3 的11个位点发生突变，其中8 个突变位点是错义突变（MS），均可导致氨基酸的改变；2 个突变位点是同义突变（SS），氨基酸未发生改变；1 个突变位点发生移码突变（FS），造成氨基酸读码框顺序的改变，并产生新的终止密码子，使蛋白发生截短，造成功能缺失。在5/50例（10%）乳腺癌组织中检测到外显子4 的12个位点发生突变，其中6 个为错义突变（MS），均可导致氨基酸的改变；6 个移码突变（FS），突变热点在221 位碱基，发生率最高（33%）。 外显子6、7 和剪接点未见突变。在正常人外周血淋巴细胞、正常乳腺组织、癌旁和非癌旁乳腺增生组织中均未检测到该基因突变。2）在12/50例（24%）乳腺癌，5/50例（10%）乳腺癌旁增生，3/50例（6%）乳腺良性增生，3/50例（6%）正常乳腺组织和1/15例（6.7%）正常人淋巴细胞检测到GSTP1 基因外显子5 第313 核苷酸多态性（A→G，导致Ile105Val）。 结论:研究结果提示:1）GSTP1 基因外显子突变可能与部分乳腺癌的发生有关；2）GSTP1 第5 外显子的多态性与乳腺癌易感性可能有关。      

FHIT和p16基因甲基化与肺癌的发生

背景与目的:探讨FHIT和p16基因甲基化与肺癌发生之间的关系. 材料与方法:采用甲基化特异性PCR检测59例原发性肺癌组织,相对应的32例正常组织及11例支气管鳞状化生组织中FHIT基因、p16基因启动子区CpG岛甲基化状况.结果:肺癌组织和正常肺组织中的FHIT基因甲基化率分别为37.3%(22/59)、0.0%(0/32),两组间的差异有统计学意义(P<0.01);支气管鳞状化生组织FHIT基因甲基化阳性率为18.1%(2/11).肺癌组织和正常肺组织中的p16基因甲基化率分别为50.8%(30/59)、0.0%(0/32),两组间的差异具有统计学意义(P<0.01);支气管鳞状化生组织p16基因甲基化阳性率为18.1%(2/11).肺癌患者吸烟组中FHIT、p16基因甲基化联合检测的阳性率为90.6%(29/32),与非吸烟组(33.3%.9/27)相比较,其差异具有统计学意义(P<0.05).结论: FHIT基因和p16基因启动子区甲基化可能与肺癌的发生有关.     

乳腺癌特异性标志物人乳腺小黏蛋白的检测及临床意义

目的通过检测乳腺癌特异性的标志物人乳腺小黏蛋白（hSBEM）在良、恶性乳腺组织及外周血中表达，探讨其作为乳腺癌细胞血行转移标志物的可能性。方法应用巢式逆转录聚合酶链反应（nested-RT-PCR）技术，对67例乳腺癌、癌旁正常乳腺组织，16例乳腺良性肿瘤组织和患者外周血，以及20位健康志愿者外周血hSBEM的表达进行检测；同时分析胃癌、大肠癌、食管癌、肺癌和卵巢癌各5例组织中hSBEM的表达情况。结果hSBEM在乳腺癌、乳腺良性疾病及正常乳腺组织中的表达分别为92．54％（62／67）、87．50％（14／16）及88．05％（59／67），3组间差异无统计学意义（P〉0．05）；hSBEM在非乳腺癌的其他癌组织中无表达。67例乳腺癌患者外周血hSBEM检出率为50．75％（34／67），转移性及伴淋巴结转移乳腺癌患者外周血中hSBEM表达率明显高于局限性乳腺癌及无淋巴结转移者（P〈0．05）；hSBEM在健康人及乳腺良性疾病患者外周血中均无表达。hSBEM的表达与患者的年龄、原发肿瘤大小、病理类型、ER和PR的状态无关（P〉0．05）。结论hSBEM特异性表达于乳腺组织，乳腺癌患者外周血检测出hSBEM提示已有癌细胞进入血液循环，因此可作为检测乳腺癌血行微转移的标志物。     

Analysis of FHIT Gene Methylation in Egyptian Breast Cancer Women: Association with Clinicopathological Features

Background: Fragile histidine triad (FHIT) gene is a tumor suppressor gene which involved in breast cancerpathogenesis. Epigenetics alterations in FHIT contributes to tumorigenesis of breast cancer. Objective: Ourobjective was to study FHIT promoter region hypermethylation in Egyptian breast cancer patients and itsassociation with clinicopathological features. Materials and Methods: Methylation-specific polymerase chainreaction was performed to study the hypermethylation of FHIT promoter region in 20 benign breast tissues and30 breast cancer tissues. Results: The frequency of hypermethylation of FHIT promoter region was significantlyincreased in breast cancer patients compared to bengin breast disease patients. The Odd´s ratio (95%CI) ofdevelopment of breast cancer in individuals with FHIT promoter hypermethylation (MM) was 11.0 (1.22-250.8).There were also significant associations between FHIT promoter hypermethylation and estrogen, progesteronereceptors negativity, tumor stage and nodal involvment in breast cancer pateints. Conclusions: Our resultssupport an association between FHIT promotor hypermethylation and development of breast cancer in Egyptianbreast cancer patients. FHIT promoter hypermethylation is associated with some poor prognostic features ofbreast cancer.     

Genetic alterations of the WWOX gene in breast cancer

FRA3B and FRA16D are the most sensitive common chromosomal fragile site loci in the human genome and two tumor suppressor genes FHIT (Fragile Histidine Triad) and WWOX (WW domain-containing oxidoreductase gene) map to this sites. The WWOX gene is composed of 9 exons and encodes a 46-kD protein that contains 414 amino acids. Loss of heterozygosity, homozygous deletions, and chromosomal translocations affecting WWOX has been reported in several types of cancer, including ovarian, esophageal, lung and stomach carcinoma, and multiple myeloma. The aim of this study was to determine the role of WWOX as a tumor suppressor gene in patients with breast cancer. Tumor and adjacent non-cancerous tissue samples were obtained from 81 patients with breast cancer. DNA was isolated from all tissue samples, and all exons and flanking intronic sequences of the WWOX gene were analyzed by PCR amplification and direct sequencing. We detected 14 different alterations in the coding sequence and one base substitution at the intron 6 splice site (+1 G-A). In addition to exonic and splice-site alterations, we detected 23 different alterations in the non-coding region of the gene. All coding region mutations identified in this study were in the exons between 4 and 9. We did not observe any alterations in exons 1-3. We conclude that mutations in critical region of the WWOX gene are frequent and may have an important role in breast carcinogenesis.     

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.     

FHIT基因在乳腺癌组织中的异常甲基化和表达

目的：检测FHIT基因在乳腺癌组织中的异常甲基化和表达,探讨其在乳腺癌发生发展中的作用。方法：收集乳腺癌新鲜组织标本和配对的癌周正常乳腺标本共90例,采用甲基化特异性PCR和免疫组织化学的方法检测FHIT基因的异常甲基化和蛋白表达。结果：90例乳腺癌组织中,有38例发生了甲基化,阳性率为42％。FHIT基因的甲基化和乳腺癌的临床分期相关,P〈0．01,和淋巴结转移状况不相关,P〉0．05。32例表达FHIT蛋白,阳性率为36％。FHIT蛋白表达和乳腺癌的临床分期以及淋巴结转移状况相关,P〈0．05。FHIT基因的异常甲基化和蛋白表达呈负相关,P〈0．05。结论：FHIT基因的异常甲基化和蛋白失表达是乳腺癌发生、发展过程中的频发事件,两者可以作为预测乳腺癌发展进程的有效标志。甲基化可能是引起FHIT基因失活并进而导致乳腺癌发生的重要机制。     

Mutation analysis of EP300 in colon,breast and ovarian carcinomas

The putative tumour suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. We analysed 203 human breast, colon and ovarian primary tumours and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumours but no somatic mutations in EP300 were identified in any primary tumour. Analysis of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). We confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbours an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot analysis confirmed the presence of an apparently wild-type protein. Our study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harbouring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumour types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.     

原位杂交法检测SNCG在乳腺组织中的表达

目的:检测乳腺癌相关基因SNCG在乳腺组织不同病变的阳性表达率,分析其表达规律,探讨其在乳腺癌发生、发展中的作用。方法:用原位杂交方法,以地高辛标记的SNCG反义mRNA作探针,检测167例乳腺不同病变组织中SNCG基因mRNA的表达情况,并进行统计学分析。结果:SNCG的阳性表达率在乳腺增生症为76.0%(38/50),纤维腺瘤为20.0%(3/15),非典型性增生为92.3%(12/13),乳腺癌组织为95.5%(85/89),并且表达强度不同。有淋巴结转移的乳腺癌中强阳性表达率为47.7%(21/44)。而乳腺增生症组中无强阳性表达者。SNCG在不同乳腺病变组织中的表达有统计学意义(P<0.001)。结论:SNCG作为一个新发现的乳腺癌相关基因,在乳腺不同病变中表达情况不同,随病变程度加重,表达率明显增高。有转移者表达强度明显增强。因而SNCG可作为判断乳腺癌恶性潜能的指标。     

Loss of FHIT expression in breast cancer is correlated with poor prognostic markers.

OBJECTIVE: The fragile histidine triad (FHIT) gene is a putative tumor suppressor gene that is thought to be involved in the carcinogenesis of breast cancer. Loss of FHIT expression has been observed in up to 72% of breast cancers and has been associated with increased p53, a high proliferation index, and increased tumor size and grade. However, loss of FHIT expression has not been investigated in association with apoptosis and cyclooxygenase-2 (COX-2) expression in breast cancer. Furthermore, expression of FHIT in primary breast tumors and their metastatic axillary lymph nodes has also not been previously described. The purpose of this study was to evaluate the expression of FHIT, COX-2, bcl-2, and p53 in primary breast tumor tissue; correlate their expression with known clinical and pathologic markers; and in cases when tissue was available, evaluate the expression of FHIT and COX-2 in the corresponding metastatic axillary lymph node in the same patient. METHODS: Primary breast tumor specimens from 80 patients were examined for the presence of FHIT, COX-2, bcl-2, and p53 expression by immunohistochemistry using standard methods. When tissue was available, the expression of FHIT and COX-2 was also evaluated in the corresponding metastatic axillary lymph node specimen. RESULTS: FHIT expression in primary breast tumors was 56%. There was a significant correlation between FHIT expression in primary breast tumor and bcl-2 expression (P = 0.017). We also observed a significant inverse correlation between FHIT expression in primary breast tumor tissue and p53 expression (P = 0.023) in lymph node-negative cases. A significant inverse correlation between FHIT expression in the primary tumor and Ki-67 (P = 0.009) was also observed in lymph node-negative cases. FHIT expression in primary tumors correlated with FHIT expression in the metastatic lymph node (52.5%; P = 0.001). FHIT expression in primary tumors did not correlate with COX-2 expression. CONCLUSION: Our results suggest that loss of FHIT expression in breast cancer is associated with poor prognostic features. Furthermore, loss of FHIT expression is also seen in metastatic axillary lymph node. The prognostic and predictive value of these findings needs to be further evaluated in larger trials with longer follow-up.     

Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer.

Changes which lead to excessive cyclin production or to loss of cell cycle inhibition by proteins such as p16/MTS1 may release breast tumour cells from the constraints of cell division. In order to establish the frequency of MTS1/p16 gene alteration and its relation with genetic damage to the p53 and cyclin D1 genes, we have studied these gene abnormalities in 164 human primary breast cancers and in six breast cancer cell lines. Two breast cancer cell lines and one primary tumour showed a homozygous deletion of exon 2 of the MTS1 gene. Using single-strand conformation polymorphism and subsequent sequencing analysis, one tumour showed an alteration at codon 67 (CCC-->CTC; Pro to Leu). Another tumour showed a mutation at codon 98 (without amino acid change) with an additional polymorphism at codon 140. This polymorphism was also found in 13 other tumour samples, but has no effect on (disease-free) survival. From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.     

Mutation profile of the p53, fhit, p16INK4a/p19ARF and H-ras genes in Indian breast carcinomas

Breast cancer is the second most prevalent cancer affecting Indian women. Genetic alterations of oncogenes and tumor suppressor genes were attributed to the development of breast carcinomas. In the present study, human breast tumor DNAs from untreated, non-familial, Indian patients were analysed for the presence of mutations in p53, fhit, p16INK4a/p19ARF and H-ras genes. Polymerase chain reaction-single strand conformation polymorphism and sequencing analysis were used to detect point mutations. Exons 5-8 of p53, exons 1-2 of p16INK4a, exon 2 of p19ARF, exons 5-9 of fhit gene and exons 1-2 of H-ras genes were amplified and analysed individually using exon-flanking primers. Only 12% of the tumors had mutation in p53, 8% had mutation in fhit gene and none of the tumors showed evidence for mutation in p16INK4a/p19ARF and H-ras genes. Tumor B18 exhibited two novel mutations in the p53 gene, ATGright curved arrow GTG (Metright curved arrow Val) at codon 237 and AATright curved arrow GAT (Asnright curved arrow Asp) at codon 263. Both of these mutations are hitherto unreported in breast carcinomas. Tumor B20 had a non-sense mutation CGAright curved arrow TGA (Argright curved arrow Stop) at codon 306 of p53 gene. In fhit gene, tumor B1 exhibited TTCTright curved arrow TACT mutation at intron 8 and tumor B15 had a silent mutation GAGright curved arrow GAA (Gluright curved arrow Glu) at codon 123. Our results indicate that, among the genes analysed, the p53 gene was more frequently mutated than fhit, p16INK4a/p19ARF and H-ras genes in Indian mammary tumors. Transcribable point mutations of fhit gene were found to be extremely uncommon in these tumors. Mutations in the above genes are mutually exclusive and are infrequent in fhit, p16INK4a/p19ARF and H-ras genes suggesting that these genes may not play a major role in Indian breast carcinomas. However, the significant frequency of mutations in the p53 gene suggest that p53 could be one of the genes involved in the genesis of sporadic breast carcinomas in Indian women.     

p53 Alterations and protein accumulation in benign breast tissue and breast cancer risk: a cohort study.

Disruption of p53 gene function seems to have a pivotal role in carcinogenesis. p53 gene changes occur before the development of breast cancer and therefore might influence breast cancer risk. We investigated the association between p53 protein accumulation and p53 mutations detected in benign breast tissue and risk of subsequent breast cancer. We conducted a case-control study nested within the cohort of 4,888 women in the Canadian National Breast Screening Study who were diagnosed with biopsy-confirmed benign breast disease during active follow-up. Cases were women with benign breast disease who subsequently developed breast cancer; five controls were matched to each case. p53 protein accumulation was assessed immunohistochemically using sections of paraffin-embedded benign breast tissue from 104 cases and 385 controls; for 82 of these cases and 327 of the controls, DNA was successfully extracted from the breast tissue for p53 gene analysis using PCR-single-strand conformation polymorphism/direct sequencing. p53 protein accumulation was associated with a 2-fold increase in risk of progression to breast cancer [adjusted odds ratio (OR), 2.16; 95% confidence interval (95% CI), 1.08-4.30], whereas p53 nucleotide changes overall were not associated with altered risk (adjusted OR, 1.22; 95% CI, 0.68-2.19); those with both p53 immunopositivity and a p53 nucleotide change had an OR (95% CI) of 3.20 (1.21-8.50). Nonpolymorphic intronic changes were associated with a 2.8-fold increase in risk (OR, 2.84; 95% CI, 1.09-7.41). The results of this study suggest that p53 protein accumulation and nonpolymorphic intronic changes in p53 are associated with increased risk of progression to breast cancer in women with benign breast disease.     

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。     

结晶型NiS诱发恶性转化细胞中的p16基因和FHIT基因的变化

目的 检测结晶型NiS诱发永生化人支气管上皮细胞系(16HBE)恶性转化过程中脆性组氨酸三联体基因(FHIT)和p16基因的变化,探讨镍化合物致癌的分子机制。方法 采用RT-PCR、DNA序列分析、银染PCR—SSCP方法检测恶性转化细胞、成瘤细胞中FHIT基因和p16基因的变化。结果 与对照组16HBE相比,转化细胞、成瘤细胞p16基因第2外显子、第2-3外显子末见突变,mRNA表达末见异常;FHIT基因第5,6,7,8外显子及第1-4外显子、第5-9外显子末见突变,但发现转化细胞、成瘤细胞FHIT基因的mRNA失表达或出现异常转录本;对其中FHIT基因第5-9外显子的一异常转录本测序分析显示,FHIT第6,7,8外显子缺失,第5,9外显子异常拼接,且中间插入一个36bp的小片段。结论 在结晶型NiS诱发16HBE恶性转化过程中,p16基因在DNA和mRNA水平末见异常改变,提示p16基因在镍致癌过程中可能不发挥作用;FHIT基因在mRNA水平出现缺失或异常转录本,表明FHIT基因在镍致癌过程中可能发挥一定作用;镍诱导的FHIT基因异常,可能是将外源致癌物、染色体脆性部位不稳定性和细胞恶变相联系起来的一个分子事件,FHIT基因可能是镍等外源致癌物作用的主要靶基因之一。     

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     

Polymorphism at codon 213 within the p53 gene

This report describes a rare polymorphism at codon 213 (silent alteration of CGA to CGG) within the coding region of the p53 gene. The rare polymorphic allele was present in six cases out of 189 lung and breast cancer DNAs analyzed (3.2%) and resulted in the loss of a TaqI site. This allele could be mistaken for a mutation when screening methods of mutation analysis are used without comparison with normal tissue DNA.     

Analysis of germline and tumor mutations of p53 gene in familial occurrence of soft tissue sarcomas

BACKGROUND: Familial soft tissue sarcomas are extremely rare. There is little information available on the clinical features and molecular findings of the hereditary occurrence of mesenchymal tumor. PATIENTS AND METHODS: A woman and her younger brother had malignant fibrous histiocytoma (pleomorphic type) and liposarcoma (pleomorphic type) in the lower limbs, respectively. Analysis of p53 mutations in exons 5-9 of the tumor and in germ-line was done. RESULTS: A guanine to adenine substitution occurred in CGC, codon 175 of exon 5 in p53 gene, to CAC in the tumor sample of Case 1. Likewise, a thymine to cytosine substitution occurred in TTT, codon 270 of exon 8 in p53 gene, to TCT in tumor sample of Case 2. Germline mutations were not seen in the either patients. CONCLUSIONS: Different missense mutations of p53 were detected in each tumor, however no germline mutations of p53 were found. The alteration of codon 175 in Case 1 is relatively common mutation. On the contrary, the mutation in codon 270 in Case 2 was extremely rare in cancers. Further molecular investigation is needed to understand the mechanism in familial occurrence of sarcomas.     

FHIT在乳腺癌中的表达及其与临床病理指标的关系

目的研究FHIT在乳腺良、恶性疾病组织中的表达特点,分析其与乳腺浸润性导管癌临床病理指标之间的关系。方法采用免疫组化SP法检测42例浸润性导管癌、8例导管内癌、16例导管上皮不典型增生、30例乳腺病病理标本Fhit蛋白的表达水平,并对其在各组织中的表达水平进行病理学观察和半定量分析。结果 Fhit蛋白在乳腺病、导管上皮不典型增生、导管内癌及浸润性导管癌组织中的表达阳性率逐渐降低,比较差异有统计学意义（P〈0.01）。42例乳腺浸润性导管癌中有淋巴结转移组Fhit蛋白表达阳性率32.2%（8/25）,显著低于无淋巴结转移组58.8%（10/17）（P〈0.05）;临床Ⅰ期、Ⅱ期、Ⅲ期浸润性导管癌Fhit蛋白阳性表达率分别为90.0%、43.7%、12.5%,比较差异有统计学意义（P〈0.01）;Fhit蛋白的表达与Cerb-B2的表达呈负相关,γs=-0.357（P〈0.05）;Fhit蛋白的表达与p53的表达呈正相关,γs=0.411（P〈0.01）。Fhit蛋白的表达缺失与年龄、肿瘤的大小、组织学分级、ER、PR无明显相关性。结论 FHIT表达降低可能对乳腺癌的演化和进展具有一定作用;与浸润性导管癌的淋巴结转移、临床分期密切相关;与Cerb-B2、p53表达相关,可为乳腺癌的早期诊断、进一步治疗及预后判断提供理论依据。