Association of Loss of Heterozygosity at the p53 Locus with Chemoresistance in Osteosarcomas

Although the osteosarcoma is considered to be among the most chemosensitive malignancies and preoperative chemotherapy is commonly applied, an appreciable proportion of cases are in fact quite insensitive. Predictive markers for chemosensitivity are therefore desirable in order to develop effective treatment strategies. Thirty-two cases of conventional osteosarcomas treated at the Cancer Institute Hospital, Tokyo, were analyzed. The sensitivity to preoperative chemotherapy was investigated with reference to loss of heterozygosity (LOH) at the 17p13 ( p 53) and 13q14 ( Rb ) loci and expression of the cell-cycle associated proteins, p53, Rb, p21/Waf-1, mdm-2 and Ki-67, as detected immunohistochemically. LOH was detected by analyzing polymerase chain reaction products at marker microsatellite loci. The efficacy of chemotherapy was evaluated both radiologically and histologically. LOH at p 53 or Rb loci was seen in 54% (13/24) and 58% (14/24) of cases, respectively. Only 15% of osteosarcomas with LOH at the p 53 locus were sensitive to preoperative chemotherapy, as compared to 64% of tumors without such loss ( P <0.05). A similar but much less distinct tendency was observed with LOH at the Rb locus. No relationship was evident between chemosensitivity and immunohistochemical staining patterns for p53, Rb, p21/Waf-1, mdm-2 or Ki-67. The results suggest that p 53 gene deletion, but not the other parameters investigated, may be useful for predicting chemoresistance of osteosarcomas.     

Comparative genomic hybridization of postirradiation sarcomas.

BACKGROUND: Radiotherapy is a known risk factor for sarcoma development. Postirradiation sarcomas arise within the radiation field after a latency period of several years and usually are highly malignant. Very little is yet known about their genetic changes. METHODS: Twenty-seven postirradiation sarcomas were analyzed by comparative genomic hybridization, which allows genome-wide screening of DNA sequence copy number changes. RESULTS: Copy-number aberrations were detected in 20 (74%) tumors. The mean number of aberrations per tumor was 5.3 with gains outnumbering losses. The most frequent gains affected the minimal common regions of 7q11.2-q21 and 7q22 in 30% and 7p15-pter in 26%. Gain of 8q23-qter was detected in 22%. The most frequent losses affected 11q23-qter and 13q22-q32 in 22%. In osteosarcomas, the most frequent aberration was loss of 1p21-p31, in malignant fibrous histiocytomas (MFH) gain of 7cen-q22, and in fibrosarcomas gain of 7q22. The findings in postirradiation osteosarcomas and MFHs were compared with findings in sporadic osteosarcomas and MFHs, reported previously by the authors. In sporadic osteosarcomas, gains outnumbered losses, but, in postirradiation osteosarcomas, losses were more frequent than gains. Loss at 1p was rare in sporadic osteosarcoma (3%) but frequent (57%) in postirradiation osteosarcomas. Gains at 7q were frequent both in postirradiation and sporadic MFH. CONCLUSIONS: According to previous studies on different types of sporadic sarcomas, gains at 7q or 8q are associated with poor prognosis or large tumor size. Thus, the frequent gains at 7q and 8q might have been responsible in part for the poor prognosis of postirradiation sarcomas. Also, however, some of their clinical features, i.e., high malignancy grade, late diagnosis, and central location, are associated with a poor prognosis.     

Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas

Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal aberrations in osteosarcomas were analyzed by comparative genomic hybridization (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS) protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6 relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The median number of changes was 16 and 12 in primary and relapsed osteosarcomas, respectively. The median number of aberrations in primary high-grade osteosarcomas (17.0) was significantly higher than in low- or intermediate-grade osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q, 1p21-p31 and 1q21-q24, and the most frequent losses were 10q, 5q and 13q. High-level gains were observed on 8q23-q24, 17p13 and 1q21-q24. A gain of 19p (p < 0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in good responders. Univariate analysis revealed that patients with primary metastases (p = 0.002), poor histologic responses (p = 0.005), high-level gains of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event-free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of 10q21-22 (p = 0.017) had significantly higher EFS than patients without these aberrations. Multivariate analysis demonstrated that primary metastasis, loss of 13q14 and loss of 5q were independent prognostic factors. The findings of our study seem to be useful for evaluating the prognosis of patients and may finally lead to treatment strategies based on genetic background of osteosarcoma.     

P53 overexpression as an indicator of overall survival and response to treatment in osteosarcomas

The p53 gene located at chromosome 17pl3 is found to be altered (allelic loss or other mutation) in multiple human cancers, including osteosarcomas. The mutated gene produces a protein with a prolonged half-life thus rendering it detectable by conventional immunohistochemistry. We examined the correlation between p53 expression and clinical prognosis as well as response to therapy. Twentyone patients with previously untreated and histologically verified highly malignant osteosarcoma were used for this study. Biopsy material taken both prior to the start of COSS 91 protocol and at the time of surgery (ten weeks later) was examined for alterations in p53 protein expression and drug resistance. Two patients who had strong (+++) p53 protein expression and three others who became positive during the chemotherapy had significantly worse prognosis (all of them died within one year) than those who showed no p53 expression both at biopsy and after chemotherapy (all 11 patients are alive, average follow-up time: 3.5 years). All patients who showed any kind of positive p53 protein expression on initial biopsy were non-respon-ders to chemotherapy. In contrast, 69% (9 out of 13) of those who exhibited no p53 expression on initial biopsy were responders or intermediate responders to chemotherapy. We concluded that p53 expression may be a useful prognostic factor in osteosarcomas. The direct correlation between p53 positive expression and resistance to therapy can help in identifying patients who are in need of a more vigorous or different chemotherapeutical protocol.     

Loss of Heterozygosity for Loci on Chromosome Arms 1p and 10q in Oligodendroglial Tumors: Relationship to Outcome and Chemosensitivity

Oligodendroglial tumors frequently have deletions of chromosomal loci on 1p and 19q. Loss of heterozygosity (LOH) of chromosome 10 may be a negative prognostic factor. We reviewed 23 patients with oligodendroglial tumors, to evaluate the frequency of 1p and 10q LOH and correlate with clinical outcome. Three loci (D1S402, D1S1172, MCT118) on 1p and 2 loci (D10S520 and D10S521) on 10q were analyzed for LOH using PCR techniques. Sixteen oligodendrogliomas (6 low grade and 10 anaplastic) and 7 oligoastrocytomas (1 low grade and 6 anaplastic) were studied. Overall 14/22 (64%) showed 1p LOH and 7/23 (30%) showed 10q LOH. Of 7 patients with some response to chemotherapy, all showed 1p LOH and none had 10q LOH. Of 5 patients with stable or progressive disease, 1 had 1p LOH and 2 showed 10q LOH. The presence of 1p LOH was significantly associated with response to chemotherapy (p = 0.02). Median progression free survival (PFS) was 31 months for 1p intact patients and 118 months for the 1p LOH group (p = 0.014). Median PFS for 10q LOH patients was 31 and 118 months for patients with intact chromosome 10 (p = 0.016). 1p LOH is a predictor of response to chemotherapy and a good prognostic factor. 10q LOH is less common in oligodendroglial tumors but predicts for worse outcome. Molecular genotyping of oligodendroglial tumors is recommended as part of the standard diagnostic workup.     

Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis

Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb-pathway components is a frequent event in cancer. In concert with the inactivation of cell death pathways, such events not only contribute to tumor development but also determine the intrinsic and acquired resistance to cancer therapy and, ultimately, disease prognosis. We previously observed that the cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog Bax are positive prognostic factors and identify patients with good prognosis in esophageal squamous cell carcinoma (SCC). In the present study, we therefore extend our analysis to additional genes controlling the G(1) restriction point and apoptosis, respectively. This retrospective analysis was performed in a cohort of 53 patients undergoing surgery for esophageal SCC with curative intent, i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb, p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were associated individually with shorter overall survival, while Bcl-2 expression and p53 mutation were not of prognostic relevance. The longest survival was observed in a subgroup of patients whose tumors bore a combination of favorite genotypes, i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein expression. These results show that multigene analyses based on limited sets of functionally linked genes reliably identify patients with good vs. poor prognosis.     

DNA sequence copy number increase at 8q: a potential new prognostic marker in high-grade osteosarcoma

Histologic response to chemotherapy is currently the best prognostic parameter in high-grade osteosarcoma but it can be evaluated only after several weeks of chemotherapy. Thus a prognostic parameter known at the time of diagnosis would be of great clinical benefit. In the present study, we present the results of 31 primary high-grade osteosarcomas analyzed by comparative genomic hybridization (CGH). CGH allows for genome-wide screening of a tumor by detecting alterations in DNA sequence copy number. The most frequent aberrations were copy number increases at 1q21 in 58% of the tumors and at 8q (8q21.3-q22 in 52% and 8cen-q13 in 45%), followed by copy number increases at 14q24-qter (35%) and Xp11.2-p21 (35%). The most common losses were detected at 6q16 (32%) and 6q21-q22 (32%). Patients with a copy number increase at 8q21.3-q22 and/or at 8cen-q13 had a statistically significant poor distant disease-free survival (p = 0.003) and showed a trend toward short overall survival (p = 0.04). Patients with a copy number increase at 1q21 showed a trend toward short overall survival (p = 0.04). Thus, specific genetic aberrations detected at the time of the diagnosis could be used in prognostic evaluation of high-grade osteosarcoma.     

KIT gene in pediatric osteosarcomas: Could it be a new therapeutic target?

In our previous study, a frequent rearrangement at 4q12 has been identified by allelotyping in our large and homogeneous population of pediatric osteosarcomas and it was significantly linked to c-kit protein overexpression. To confirm and understand the involvement of KIT in this tumor, the next step of the study was designed to detect the potential mutations of KIT gene by sequencing the frequently mutated exons 6, 8, 10, 11, 13, 17 and 21 and, in case of unmutated samples, to confirm the genomic amplifications of the wild-type receptor by real-time quantitative PCR (QPCR). A new microsatellite and QPCR targeting PDGFRA was also added to check the accuracy of the 4q11-12 locus. These techniques were performed in 74 pediatric high-grade osteosarcomas treated with the OS94 protocol. Surprisingly, no mutations were found, but, only DNA amplification of KIT gene in the entire population. PDGFRA gene QPCR revealed an unexpected result of predominant deletions in the rearranged tumors. All these results confirm the major role of the 4q11-12 locus and specifically the involvement of c-kit wild-type receptor overexpression in pediatric osteosarcomas and leads us to believe that inhibitors targeting this receptor could have a therapeutic effect in a selected group of patients.     

Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs.     

Prognostic significance of p21waf1, cyclin D1 and retinoblastoma expression detected by immunohistochemistry in non-small cell lung cancer.

p21waf1 is a downstream effector of p53, and mediates growth arrest by inhibiting the action of G1 cyclin-dependent kinases. Cyclin D1 is a cell-cycle regulator essential for G1 phases progression and a candidate proto-oncogene implicated in the pathogenesis of several human tumor types. Cyclin D1 overexpression and the absence of retinoblastoma (Rb) protein have been frequently seen in various types of cancer, including lung cancer. The aim of this study was to clarify the relationship between the expressions of p21waf1, cyclin D1, and Rb protein, and to investigate the correlation between these protein expressions and the clinical features of the patients, and their prognoses. We immunohistochemically examined 92 samples of resected non-small cell lung cancer for p21waf1, cyclin D1, and Rb expression. Of the 92 specimens examined, 43 cases (46.7%) showed p21waf1 expression, 23 cases (25.0%) showed cyclin D1 overexpression, and 61 cases (66.3%) showed Rb expression. No correlation was observed between the expressions of p21waf1, cyclin D1, and Rb. There was no association of p21waf1 and cyclin D1 immunoreactivity with gender, disease stage, or histological types of the tumor. Regarding the prognosis in 79 cases with complete resection, no statistical differences were observed according to the degree of expression of these three factors. However, when unfavorable prognostic factors were considered to be the positive expression of p21waf1, positive of cyclin D1, and negative of Rb, the 5-year disease-free survival rate in the group with 2 or 3 unfavorable prognostic factors was 21.1%, which was statistically poorer than the 45.4% in the group with 0 or 1 unfavorable prognostic factor (p=0.0138). We conclude that examination of the expression of cell cycle regulators, such as p21waf1, cyclin D1, and Rb, is useful as a prognostic indicator, when these proteins' expression is analyzed in combination.     

Lack of correlation between survival and allele loss on chromosome 7q31–32 in primary breast cancer

High incidence of loss of heterozygosity (LOH), affecting the 7q31–32 chromosome region in sporadic primary human breast carcinomas suggests the presence of a tumor suppressor gene in this region which seems relevant to the development of breast cancer. To further determine the possible role of this region in the pathogenesis of human primary breast cancer and association with survival, LOH analysis was performed on 52 primary breast cancer patients using a set of highly polymorphic microsatellite markers. Our panel contained twenty biopsy cases of unknown survival, nineteen cases with more than five years survival and fourteen cases with less than two years survival. Corresponding normal and tumor DNAs were analyzed by polymerase chain reaction (PCR). The data presented here demonstrate that all patients were informative at least at one locus and 20 (38%) out of 53 cases showed LOH at one or more loci on chromosome 7q31–32. Relatively high incidence of LOH (34%) was detected at the D7S522 microsatellite marker located near to the cMet proto-oncogene while lower frequencies were observed at D7S523 (19%) and D7S495 (17%) loci, supporting the existence of a putative tumor suppressor gene at the chromosome 7q31.1 region. Our results suggest that allelic imbalance on 7q may occur at an early stage of breast carcinogenesis, as no correlation was observed between allelic loss and clinico-pathological data. This work was supported by Hungarian Research Grants ETT (T-019307) and OMFB (04-1-99-94-0328) given to Edith Olah.     

iFISH技术检测多发性骨髓瘤遗传学异常及其临床意义

目的:采用iFISH技术了解多发性骨髓瘤染色体异常情况,分析染色体异常与多发性骨髓瘤部分临床资料、治疗效果及预后之间的关系。方法:采用组合探针（1q21、DLEU/RB1、p53、IGH）对94例初诊MM患者骨髓细胞进行iFISH检测,分析其细胞遗传学异常,探讨其与临床资料及治疗效果之间的关系,明确其预后价值。结果:94例患者中,74例（78.72%）检测出1种及1种以上细胞遗传学异常;其中1种异常的34例（34/74,45.95%）,2种异常的15例（15/74,20.27%）,25例存在3种及3种以上异常（25/74,33.78%）。其异常的比例从高到低分别为:p53缺失（45/74,60.81%）,1q21扩增（44/74,59.46%）,IGH重排（31/74,41.89%）,DLEU/RB1缺失（28/74,37.84%）。分析发现,p53缺失与血小板计数、白蛋白及球蛋白水平有关,IGH重排与白蛋白及瘤细胞负荷有关,DLEU/RB1缺失与血红蛋白、血沉、白蛋白及球蛋白水平有关,未发现1q21扩增与各项临床指标之间的关系。将患者按照治疗方案分为VAD组和硼替佐米组,结果显示VAD组中iFISH阴性者的疗效明显优于iFISH阳性者,而在硼替佐米组未发现FISH阳性者和阴性者的疗效有差异。生存分析发现,IGH重排与总生存时间相关,而p53缺失与总生存时间和无病生存时间均明显相关,为MM患者的独立预后因素。结论:多数MM患者存在细胞遗传学异常;1q21扩增、p53缺失及IGH重排的发生率较高;细胞遗传学异常与多种不良临床指标相关,并与临床治疗反应性相关,存在异常者治疗效果欠佳,预后较差。     

Predictive effect of p53 and p21 alteration on chemotherapy response and survival in locally advanced adenocarcinoma of the esophagus

BACKGROUND: Cell cycle regulating proteins (p53/p21) and proliferation index Ki-67 have been associated with prognosis and response to chemotherapy. The aim of this study was to determine the significance of these molecular markers on tumor response and prognostic effect in a group of esophageal cancer patients treated with neoadjuvant chemotherapy. PATIENTS AND METHODS: Immunohistochemical expression of p53/p21 and Ki-67 was examined in pre-treatment biopsy specimen of 30 patients, in phase II neoadjuvant studies for locally advanced adenocarcinoma of the esophagus, who underwent surgery. Seven patients (23%) had progressive disease. Resection was achieved in all responders (n=23; 77%) and histochemical expression of the above-mentioned proliferating markers was examined in pre-treatment and resection specimens after chemotherapy. RESULTS: Responders had a significantly better survival compared to non-responders (p=0.001). Expression of p53, p21 and high Ki-67 in pre-treatment specimens was 73% (22/30), 63% (19/30) and 30% (10/30), respectively and was not related to response to chemotherapy. However, alteration in expression of p53-positivity in the pre-treatment specimens to p53-negativity in the resection specimens and p21-negativity to p21-positivity in 6 of the 23 (26%) resected tumors was correlated with better response and survival (p=0.011). CONCLUSION: Data from this study showed that alteration of p53 and p21 expression rather than the initial expression seems to be related to chemotherapy response and overall survival in patients with esophageal adenocarcinoma.     

Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract

BACKGROUND: The molecular pathogenesis of poorly differentiated endocrine carcinomas of the gastrointestinal tract (GI PDECs) remains unclear. It has been suggested that these lesions either originate from multipotent stem cells that also can serve as the origin of nonendocrine adenocarcinomas or arise due to the dedifferentiation of well-differentiated endocrine carcinomas (WDECs). METHODS: Ten gastric and 9 colorectal PDECs, 9 gastric WDECs, and 12 colorectal carcinomas (CRCs) were analyzed for loss of heterozygosity (LOH) at 11q13 (MEN1), 17p13.1 (p53), 3p14.2 (FHIT), 3p21.3 (RASSF1A), and 18q23 (DCC/DPC4/Smad2), and for immunohistochemical expression of p53, FHIT, Rb, and p16. RESULTS: PDECs exhibited high fractional allelic loss (FAL; 0.49), with frequent (> 40%) alterations in p53, Rb, MEN1, FHIT, and 18q. No significant differences were found between gastric and colorectal PDECs. Gastric WDECs also exhibited high FAL (0.44), with frequent alterations in Rb and/or p16, MEN1, and 3p21. CRCs exhibited a low level of FAL (0.23), with frequent (> 50%) p16 and p53 alterations. When gastric PDECs and WDECs were compared, substantial similarities were found with respect to FAL (0.42 vs. 0.44) and with respect to individual gene alterations, except in p53, which was consistently altered only in PDECs. CRCs, which were characterized by a lower FAL (0.56 vs. 0.23) and which lacked alterations in both 3p and Rb, were found to be significantly different from colorectal PDECs. CONCLUSIONS: GI PDECs demonstrated a high level of chromosomal instability; consistent inactivation of both the p53 and p16/Rb pathways; and frequent LOH at 3p (possibly involving FHIT), the MEN1 locus, and 18q. The profile of genetic alterations in PDECs was more consistent with the profile in WDECs than with the profile in CRCs.     

人骨肉瘤中Rb和p~(53)基因mRNA的表达

研究Rb和p53基因与国人骨肉瘤的关系。方法：用原位杂交技术检测Rb和p53基因mR－NA在30例国人骨肉瘤标本中的表达。结果：RbmRNA阳性16例（53．3％），阴性14例（46．7％）；p53mRNA阳性15例（50％），阴性15例（50％）。此外，骨肉瘤中Rb和p53mRNA表达呈正相关（r’s=0．462，P＜0．02）。结论：Rb和p53基因异常与骨肉瘤发生有关。     

Loss of heterozygosity of the Rb gene correlates with pRb protein expression and associates with p53 alteration in human esophageal cancer.

To understand the alterations of Rb tumor suppressor gene and the relationship between defects in the Rb and p53 pathways in human esophageal carcinogenesis, we examined the loss of heterozygosity (LOH) of the Rb gene and immunohistochemical staining of pRb protein in 56 esophageal squamous cell carcinoma specimens and related the results to the p53 gene alterations. Using four introgenic polymorphic markers as probes, we observed LOH of the Rb gene in 30 of the 55 informative tumor samples. Immunohistochemical analysis revealed different patterns of pRb expression among the tumor samples. In the 56 cases, 16 displayed extensive pRb staining comparable to that of the adjacent normal epithelia, whereas 33 showed either significantly decreased or no pRb staining and 7 had a focal staining pattern reflecting heterogeneous cancer nests in the tumor with respect to Rb status. In the tumor samples containing Rb LOH, 90% showed low or no pRb expression, whereas in samples without Rb LOH, only 20% had altered pRb expression. There was a strong association between LOH of the Rb gene and alteration of pRb expression in our samples (P < 0.0001), suggesting LOH is a main event leading to Rb inactivation. We found that Rb LOH was more frequent in tumors with p53 mutations (P < 0.05), which occurred in 31 of the 49 cases analyzed. When the status of Rb and p53 alterations was evaluated by the combined results of immunohistochemical and genetic analyses, we found that alteration of Rb and p53 had an even stronger association in our esophageal squamous cell carcinoma samples (P = 0.0015). Among the 51 cases in which both the Rb and p53 status were determined, 31 contained alterations in both genes, and only 5 and 6 cases were altered in only Rb and only p53, respectively. Our results suggest that defects in the Rb and p53 pathways and their potential synergistic effect in deregulating cell cycle and apoptosis are major mechanisms for esophageal carcinogenesis.     

p16和Rb蛋白在胃癌中的表达及其意义

目的 探讨p16和Rb蛋白与胃癌发生、发展、预后及化疗疗效的关系。方法 采用免疫组化S－P法同步检测53例胃癌组织中p16和Rb蛋白关系。结果 胃癌组织中p16和Rb蛋白表达阳性率分别为62．3％和60．4％,p16阳性和Rb阴性表达者生存率高于p16阴性和Rb阳性表达者。p16阴性和Rb阳性者术后辅助化疗复发转移率高于p16阳性和Rb阴性者。结论 p16和Rb蛋白表达,可作为辅助临床判断胃癌的生物学行为、评估疗效及推测预后的生物学指标。     

11例t(16;21)(p11;q22)急性髓系白血病病例报告并文献复习

目的:探讨11例伴t(16;21)(p11;q22)染色体易位的急性髓系白血病（acute myeloid leukemia,AML)患者的临床和实验室特点。方法:回顾性分析2007年07月至2022年03月我院收治的11例t((16;21)(p11;q22)染色体易位的AML患者临床及实验室特征并复习相关文献。结果:11例t(16;21)(p11;q22)染色体易位的白血病均为AML,FAB分型:M2型4例,M4型1例,M5型3例,AML(非M3)型3例;其中男5例,女6例。染色体R显带分析11例均可见到t(16;21)(p11;q22)染色体易位,其中9例伴有附加染色体异常。融合基因TLS/FUS-ERG检测了9例均为阳性。免疫表型除表达髓系CD34、CD117、CD33、CD13、CD38外,均表达CD56。化疗1个周期后完全缓解7例。结论:t(16;21)(p11;q22)染色体易位是一种少见的重现性染色体异常,该易位产生TLS/FUS-ERG融合基因,免疫学检测多伴CD56阳性,以AML中M2/M5型多见,化疗1个周期大部分可完全缓解,但短期内易复发,预后不良。     

P53 and rb alterations in operable breast-cancer

We analyzed association between p53 and/or Rb expression and clinicopathologic variables or Ag-NOR counts, and then ascertained whether p53 and/or Rb expression would be useful for estimating prognosis in 81 breast cancer patients. Positive p53 expression was significantly associated with post-menopausal status, axillary lymph node metastases and Ag-NOR counts, whereas low level Rb expression was significantly associated with tumor size. Moreover, the combination of p53 and Rb expression was significantly associated with Ag-NOR counts, although there was no significant association between p53 and Rb expression. In the univariate study, p53 expression as well as age and axillary lymph node metastases were significantly associated with survival, whereas Rb expression was not. In the multivariate study, p53 and/or Rb expression did not provide independent prognostic information, although axillary lymph node metastases was an important factor affecting survival. Our findings suggest that p53 and/or Rb expression may reflect tumor proliferation of breast cancer, but the prognostic value of such assays is limited.     

Allelotypes and fluorescence in situ hybridization profiles of poorly differentiated endocrine carcinomas of different sites.

PURPOSE: The aim of this work was to investigate the genotypic profiles of 36 poorly differentiated endocrine carcinoma (PDEC) of different sites to verify if their very similar phenotype may reflect similar pattern of genetic anomalies and if useful diagnostic or prognostic markers may be pointed out. EXPERIMENTAL DESIGN: All tumors were microallelotyped at 57 microsatellite on 11 autosomes and the allelotypes of a selected panel of tumors were validated by interphasic fluorescence in situ hybridization with centromeric probes for chromosomes 1, 3, 6, 11, 17, and 18 and a probe specific for p53. RESULTS: Regardless of the primary sites, PDECs exhibit very complex allelotypes (86%) and TP53 allelic imbalance (89%). Among these cases, fluorescence in situ hybridization analysis confirmed the presence of multiple aneusomies and a chromosome instability phenotype. Very low percentage of allelic imbalance (AI) and few aneuploidies were detected in only five PDECs for which an overall longer survival was observed. We found recurrent AI on 3p, 5, and 11q13 in lung PDECs, on 5q21, 8p, and 18q21 in colorectal PDECs and on 7 and 11q22 in gastric PDECs. Significantly better outcome was observed in patients with PDEC exhibiting 8q AIs and absence of AI at chromosome regions 6q25 and 6p. CONCLUSIONS: The concurrence of p53 inactivation and aneuploidies or chromosome instability are the main features of PDECs. However, the specific allelotypes observed in relation to primary site support the hypothesis that PDECs and exocrine carcinomas of all sites may share early pathogenetic mechanisms. Molecular markers of potential diagnostic and prognostic values for PDECs of different sites have been identified.