Parathyroid carcinoma,atypical parathyroid adenoma,or parathyromatosis?

BACKGROUND: Parathyroid carcinoma, atypical parathyroid adenoma, and parathyromatosis can be differentiated relatively easily from typical parathyroid adenomas, but distinguishing them from each other is more difficult. METHODS: A retrospective study of 28 consecutive patients with parathyroid carcinoma, 7 patients with atypical parathyroid adenoma, and 13 patients with parathyromatosis who were treated at the University of California at San Francisco Medical Center between 1966 and 2005 was performed. Patient demographics and clinical characteristics, indication for surgery, intraoperative findings, histopathologic characteristics, disease recurrence or persistence, site of invasion/metastases, and survival were compared in the 3 groups. RESULTS: Parathyroid carcinoma (19 of 28 patients) and atypical adenoma (4 of 7 patients) were significantly more common in men, whereas parathyromatosis was more common in women (10 of 13 patients) (P = .02). A palpable neck mass and hoarseness were almost exclusively present in patients with parathyroid carcinoma. Prior to the first parathyroid surgery, patients with parathyroid carcinoma were found to have higher blood calcium levels (>/=14 mg/dL in 16 of 26 patients [62%]), whereas only 1 of 6 patients with atypical adenoma (17%) and no patients with parathyromatosis were found to have profound hypercalcemia (P < .01). Intraoperatively, patients with parathyroid carcinoma and atypical adenoma presented with single lesions, whereas patients with parathyromatosis had multiple small lesions. Histopathologic findings were well defined in parathyroid carcinoma, but some findings overlapped in the 3 tumors studied. CONCLUSIONS: Patients with parathyroid carcinoma often differ from those with atypical parathyroid adenoma or parathyromatosis at the time of presentation because patients with parathyroid carcinoma have more profound hypercalcemia as well as invasive tumors. However, at times it is difficult to distinguish between these conditions both clinically and by final histologic examination.     

Genetic analysis of benign ovarian tumors

Ovarian cancer represents a major cause of cancer death among women and yet remarkably little is known about its etiology. The paradigm established by the colorectal carcinogenesis model would suggest that ovarian cancers are likely to arise through malignant transformation of benign ovarian tumors. However, molecular genetic data that could answer this important question is lacking. In our study, we analyzed 80 benign ovarian tumors for TP53 and K-ras mutations and for LOH on chromosomes 6, 7, 9, 11 and 17 using 56 microsatellite markers. Twenty-five percent (5/20) of non-epithelial tumors and 73% (44/60) of epithelial tumors exhibited LOH on at least 1 chromosome arm. A particularly high frequency of LOH was detected among the epithelial tumors on chromosome arms 6q (17%), 7p (17%), 7q (27%) and 11p (18%), which are also regions of frequent LOH among ovarian carcinomas. No K-ras mutations were detected in any tumor but somatic TP53 mutations were detected in 2/34 (6%) serous and 1/26 (4%) mucinous epithelial tumors. In contrast to most previous studies our data is derived from a relatively large number of microdissected tumors and is likely to represent a more accurate picture of the frequency of alterations in these tumors. We conclude that LOH is common in benign ovarian tumors, suggesting that inactivation of tumor suppressor genes are pivotal in their development. The high frequency of alterations is consistent with their being precursors to malignant disease but does not unequivocally prove this continuum. It does however provide a framework for future analysis of the molecular genetic etiology of ovarian tumorigenesis.     

Genetic and epigenetic alterations in lung tumors from bitransgenic Ki-rasG12C expressing mice

Mutations in Ki-ras occur in approximately 30-50% of patients with adenocarcinoma (AC) of the lung. We previously reported the development of a bitransgenic mouse model that expressed the human Ki-ras(G12C) allele in a lung-specific, tetracycline-inducible manner and gave rise to benign lung tumors. In the current study, these benign tumors, which represent relatively early lesions in neoplastic progression, were analyzed for molecular alterations secondary to mutant Ki-ras expression to determine the gene(s) that contribute to adenoma (AD) development. Tumors were removed following doxycycline (DOX) treatment for 9 and 12 mo and examined for alterations in cell-cycle regulatory genes. Quantification of mRNA expression for cyclin D1, retinoblastoma, p16(Ink4a), p19(Arf), and survivin was carried out by real-time PCR. All of the tumors examined exhibited a mean reduction of approximately fivefold for the retinoblastoma gene (P < 0.02). Increased expression of both p19(Arf) and survivin were detected in a majority of the tumors examined (P < 0.01 and 0.001, respectively), but no change in cyclin D1 RNA expression was observed. A subset of the lung tumors (8/28) displayed reduced levels of p16(Ink4a) expression (P = 0.02). Immunohistochemical analysis confirmed the upregulation of p19(Arf) and survivin in all 10 of the lung tumors examined. However, increased staining for cyclin D1 was observed in the tumor tissue. In addition, increased levels of activated p53 were found in lung tumor tissues stained with an anti-phospho-p53 antibody, while an absence of staining was observed with an anti-phospho-pRb antibody in both normal control and tumor tissue. Analysis of the methylation status of p16(Ink4a) by methylation-specific PCR (MSP) demonstrated that seven of eight tumors exhibiting decreased expression of p16(Ink4a) had at least partial methylation of the promoter region. Single stranded conformational polymorphism (SSCP) analysis demonstrated that neither exons 1 or 2 of p16(Ink4a) nor exons 5-8 of p53 exhibited mutations. These data thus identify alterations in specific genes and pathways that combine with the mutation in Ki-ras to promote the formation of benign lung tumors and suggest potential targets for the development of novel chemotherapeutic and chemopreventive agents during the early stages of lung tumor progression.     

肝细胞癌组织中PTEN和p27Kip1及cyclinD1蛋白表达及临床意义

目的:研究肝细胞癌(hepatocellular carcinoma, HCC)中PTEN、p27Kip1和cyclinD1蛋白的表达及相互关系,初步探讨它们在肝细胞癌的发生发展中的生物学意义。方法:应用Elivision免疫纽化方法检测53例肝细胞癌组织及癌旁肝组织中PTEN、p27Kip1和cyclinD1蛋白表达。结果: 53例肝细胞癌组织中p27Kip1和cyclinD1蛋白表达的阳性率分别为65％和53％,均高于癌旁肝组织(x2=34．11,x2=29．05,P值均为0．000),肝细胞癌组织中PTEN蛋白表达的阳性率(57％)明显低于癌旁肝组织中的阳性率(96．2％)(x2=20．94, P=0．000),PTEN和cyclinD1蛋白表达与肿瘤大小、TNM分期和是否伴肝硬化无关;与组织分化程度、有无侵袭性呈显著相关(P值分别为0．014、0．003、0．026和0．042)。p27Kip1蛋白表达与肿瘤大小和是否伴肝硬化无关,与肝细胞癌组织分化程度、TNM分期和有无侵袭性呈显著相关(P值分别为0．000、0．008和0．001)。PTEN蛋白表达与p27Kip1和cyclinD1蛋白表达无相关性。结论: PTEN、p27Kip1和cyclinD蛋白在肝细胞癌的发生发展中发挥重要作用。PTEN、p27Kip1和cyclinD蛋白的联合检测对评估肝细胞癌的恶性程度有参考价值。     

P53, cell cycle control and apoptosis: Implications for cancer

Summary Cellular proliferation depends on the rates of both cell division and cell death. Tumors frequently have decreased cell death as a primary mode of increased cell proliferation. Genetic changes resulting in loss of programmed cell death (apoptosis) are likely to be critical components of tumorigenesis. Many of the gene products which appear to control apoptotic tendencies are regulators of cell cycle progression; thus, cell cycle control and cell death appear to be tightly linked processes. P53 protein is an example of a gene product which affects both cell cycle progression and apoptosis. The ability of p53 overexpression to induce apoptosis may be a major reason why tumor cells frequently disable p53 during the transformation process. Unfortunately, the same genetic changes which cause loss of apoptosis during tumordevelopment, may also result in tumor cellresistance to anti-neoplastic therapies which kill tumor cells by apoptosis. Elucidation of the genetic and biochemical controls of these cellular responses may provide insights into ways to induce cell death and thus hopefully suggest new targets for improving therapeutic index in the treatment of malignancies.     

nm23H1和E-Cadherin在人非小细胞肺癌中的表达及临床意义

目的研究nm23H1和E-Cadherin蛋白在非小细胞肺癌(NSCLC)的表达及临床意义.方法采用S-P免疫组化法测定NSCLC中nm23H1和E-Cadherin蛋白的表达.结果有淋巴结转移的NSCLC组织中,nm23H1和E-Cadherin蛋白阳性表达率分别为29.4%(5/17)和11.8%(2/17),无淋巴结转移的则分别为82.4%(14/17)和42.9%(9/17),差异有极显著意义,P<0.01或显著意义,P<0.05.nm23H1和E-Cadherin表达与NSCLC的分期及肿瘤分化程度有关,P<0.05;基因蛋白表达在NSCLC组织中呈正相关,P<0.01.结论nm23H1和 E-Cadherin蛋白可作为判断NSCLC转移潜能及预后的重要指标.     

CDK-inhibitors-associated kinase activity: a possible determinant of malignant potential in smooth muscle tumors of the external soft tissue.

There has been accumulating histological observation of leiomyoma and leiomyosarcoma of the external soft tissue regarding their differential diagnosis. The definitive diagnostic tools have not been established, however, nor have the pathological mechanisms of cell proliferation in these tumors been clarified. Herein, expression of the cyclin-dependent kinase inhibitors (CKIs), p21, p27 and p57 and their associated kinase activities were examined in 61 cases of soft tissue smooth muscle tumors. Immunohistochemical staining showed that all 3 inhibitor proteins were expressed in all cases of leiomyoma and leiomyosarcoma, but that the mean values of their labeling indices (LIs) were higher in the cases of leiomyosarcoma. In addition, the LIs of p21 and p27 were inversely correlated in total cases. Immunoblotting revealed that these proteins are expressed at higher levels in tumors, in particular, in leiomyosarcoma. When CKIs were immunoprecipitated from tissue extracts, cyclin/cdk protein complexes associated with, at least, 1 CKI were detectable only in tumor tissues. Furthermore, cdk2 or cdk4 kinase activity manifested by these cyclin/cdk/CKI complexes (CKI-associated kinase activity) was detectable exclusively from leiomyosarcoma, but not from leiomyoma. Among the cases of leiomyosarcoma, cdk2 activity was generally found associated either with p21 or p27, but not both. Statistical analysis indicated that p21- and p27 LIs are predictive of positive or negative clinical outcome, respectively. In conclusion, the participation of CKIs in active cyclin/cdk complexes in a reciprocal and redundant manner and subsequent CKI- associated kinase activity are the characteristic profiles of malignant phenotype in these tumors. Moreover, immunohistochemical detection of CKIs may provide a useful tool for evaluating patients' prognosis.     

膀胱良、恶性上皮肿瘤中 MMP -9 的表达及临床意义简

目的：探讨MMP-9在正常膀胱组织和膀胱良、恶性肿瘤中的表达和临床意义。方法：采用免疫组织化学sP法检测15例正常膀胱黏膜、20例内翻性乳头状瘤、100例膀胱癌（包括86例膀胱尿路上皮癌、9例膀胱腺癌和5例膀胱鳞状细胞癌）中MMP-9的表达,观察其在膀胱良、恶性肿瘤中表达的差异,分析MMP-9表达与膀胱癌病理类型及临床病理特征的关系。结果：膀胱癌中MMP-9的阳性表达率为83．00％（83／100）,显著高于正常膀胱移行上皮0（0／15）及内翻性乳头状瘤35．00％（7／20）两组（P〈0．05）。MMP-9的阳性表达率随浸润深度的增加及淋巴结的转移而升高（P〈0．05）。MMP-9在膀胱尿路上皮癌中的阳性表达率较膀胱腺癌及鳞状细胞癌为高,但差异无统计学意义（P〉0．05）。结论：MMP-9在膀胱癌组织中高表达,与膀胱癌的浸润及转移密切相关,其可能在膀胱恶性上皮肿瘤的发生发展过程中发挥重要作用,并可作为预后评估的重要指标之一。     

Evaluation of magnetic resonance imaging-based radiomics characteristics for differentiation of benign and malignant peripheral nerve sheath tumors in neurofibromatosis type 1

BackgroundPatients with neurofibromatosis type 1 (NF1) develop benign (BPNST), premalignant atypical (ANF), and malignant (MPNST) peripheral nerve sheath tumors. Radiological differentiation of these entities is challenging. Therefore, we aimed to evaluate the value of a magnetic resonance imaging (MRI)-based radiomics machine-learning (ML) classifier for differentiation of these three entities of internal peripheral nerve sheath tumors in NF1 patients.MethodsMRI was performed at 3T in 36 NF1 patients (20 male; age: 31 ± 11 years). Segmentation of 117 BPNSTs, 17 MPNSTs, and 8 ANFs was manually performed using T2w spectral attenuated inversion recovery sequences. One hundred seven features per lesion were extracted using PyRadiomics and applied for BPNST versus MPNST differentiation. A 5-feature radiomics signature was defined based on the most important features and tested for signature-based BPNST versus MPNST classification (random forest [RF] classification, leave-one-patient-out evaluation). In a second step, signature feature expressions for BPNSTs, ANFs, and MPNSTs were evaluated for radiomics-based classification for these three entities.ResultsThe mean area under the receiver operator characteristic curve (AUC) for the radiomics-based BPNST versus MPNST differentiation was 0.94, corresponding to correct classification of on average 16/17 MPNSTs and 114/117 BPNSTs (sensitivity: 94%, specificity: 97%). Exploratory analysis with the eight ANFs revealed intermediate radiomic feature characteristics in-between BPNST and MPNST tumor feature expression.ConclusionIn this proof-of-principle study, ML using MRI-based radiomics characteristics allows sensitive and specific differentiation of BPNSTs and MPNSTs in NF1 patients. Feature expression of premalignant atypical tumors was distributed in-between benign and malignant tumor feature expressions, which illustrates biological plausibility of the considered radiomics characteristics.     

乳腺良恶性肿瘤及乳腺癌细胞系中SSEA-3和SSEA-4的表达

目的:探讨阶段特异性胚胎抗原SSEA-3及阶段特异性胚胎抗原SSEA-4在乳腺良恶性肿瘤及乳腺癌细胞系MDA-MB-468中的表达情况,及其与乳腺癌发生的关系。方法:通过免疫组织化学和免疫细胞化学方法检测50例乳腺癌(浸润性导管癌)病变、50例乳腺良性病变(纤维腺瘤,乳腺腺病)及乳腺癌细胞系MDA-MB-468中SSEA-3和SSEA-4的表达。结果:SSEA-3在乳腺癌中的表达阳性率为34%(17/50),且SSEA-3在乳腺癌中的表达与ER表达呈正相关(P<0.05),而在乳腺良性病变中的表达阳性率为16%(8/50);SSEA-4在乳腺癌中的表达阳性率为58%(29/50),在乳腺良性病变组织中表达阳性率为36%(18/50);SSEA-3和SSEA-4在乳腺癌中的表达均高于其在良性病变中的表达(P<0.05);且两者在MDA-MB-468细胞系中均有阳性表达。结论:SSEA-3和SSEA-4在乳腺癌良恶性病变中的表达有区别,而且在乳腺癌细胞系MDA-MB-468中表达阳性率较高,提示SSEA-3和SSEA-4的表达可能与乳腺癌的发生有关。     

EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n = 37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor alpha and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients.     

SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors,with particular utility in detection of metastatic yolk sac tumors

BACKGROUND:

The correct diagnosis of metastatic germ cell tumors is critical, because these tumors can be effectively treated and are even cured with modern therapy. Their histopathologic diagnosis can be challenging without immunohistochemical markers, which currently have limitations. SALL4 is a novel stem cell marker essential to maintain pluripotency and self‐renewal of embryonic stem cells. In the current study, the authors investigated the utility of SALL4 as a potential diagnostic marker for metastatic germ cell tumors.

METHODS:

Ninety metastatic germ cell tumors from testis, ovary, and extragonadal sites were stained with a monoclonal SALL4 antibody. In addition, 170 metastatic nongerm cell malignancies, including 158 carcinomas (6 head and neck, 8 thyroid, 12 lung, 8 breast, 7 hepatocellular, 3 cholangiocarcinomas, 2 ampullary, 10 pancreatic, 18 gastric, 15 esophageal, 10 renal cell, 10 urothelial, 12 prostatic, 18 ovarian, 6 uterine, and 13 colonic) and 12 melanomas, were also stained to test SALL4 specificity.

RESULTS:

All 22 seminomas, 7 dysgerminomas, 22 embryonal carcinomas, and 14 of 15 yolk sac tumors displayed strong and diffuse SALL positivity in >90% of tumor cells (80% of tumor cells were strongly positive in the remaining yolk sac tumor). Five of 7 choriocarcinomas and 9 of 18 teratomas were also variably positive for SALL4. In contrast, only 10 (esophageal, gastric, and colonic adenocarcinomas) of 170 metastatic somatic tumors demonstrated focally weak SALL4 reactivity (<25% tumor cells).

CONCLUSIONS:

SALL4 is a novel sensitive and highly specific marker for metastatic germ cell tumors, and is particularly useful for detecting metastatic yolk sac tumors. Cancer 2009. © 2009 American Cancer Society.     

Intrathoracic malignant peripheral nerve sheath tumors: imaging features and implications for management

Background

The aim of the study was to analyze the clinical and imaging characteristics of primary intrathoracic malignant peripheral nerve sheath tumors (MPNSTs).

Patients and methods.

In this institutional review board (IRB)-approved retrospective study, clinical and imaging features of 15 patients (eight men; mean age 50 years [range 18–83)] with pathologically proven malignant peripheral nerve sheath tumors seen from January 1999 to December 2011 were analyzed. Imaging features (CT in 15, MRI in 5 and PET/CT in 4) of primary tumors were evaluated by three radiologists and correlated with clinical management.

Results

Of the 15 tumors, six were located in the mediastinum (two each in anterior, middle and posterior mediastinum), four in chest wall, two were paraspinal, and three in the lung. Four patients had neurofibromatosis-1 (NF1); four tumors had heterologous rhabdomyoblastic differentiation (malignant triton tumor). Masses typically were elongated along the direction of nerves, with mean size of 11 cm. The masses were hypo- or isodense to muscles on CT, isointense on T1-weighted images, hyperintense on T2-weighted images and intensely fluorodeoxyglucose (FDG) avid (mean standardized uptake value [SUV]_max of 10.5 [range 4.4–23.6]). Necrosis and calcification was seen in four tumors each. Finding of invasion of adjacent structures on imaging led to change in management in seven patients; patients with invasion received chemoradiation.

Conclusions

Intrathoracic MPNSTs appear as large elongated masses involving mediastinum, lung or chest wall. Radiological identification of invasion of adjacent structures is crucial and alters therapy, with patients with invasion receiving neoadjuvant or adjuvant chemoradiation.     

Gene therapy for experimental brain tumors using a xenogenic cell line engineered to secrete hIL-2

Summary Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the feasibility and efficacy of using a rat endothelial cell line (NTC-121) transfected with the human interleukin-2 (IL-2) gene in treating experimental murine CNS tumors. The NTC-121 cells were injected intracranially in C57BL/6 mice (N = 10/group) along with non-irradiated, non-transfected B16/F10 (wild type) melanoma cells. Sixty percent of mice treated with IL-2 (p<0.001 vs. control) were long-term survivors (LTS) of >120 days. Control animals that received only wild type cells had a median survival of 18 days (range 15–20). Histopathological examination of brains from animals sacrificed at different times showed no tumor growth in the non-irradiated NTC-121 group, moderate (1–2 mm) tumor growth in the irradiated group, and gross tumor invasion (>2 mm) and tissue necrosis in the control group. Moreover, animals treated with IL-2 showed an accumulation of CD8+ T cells around the site of the injected tumor. The use of a xenogenic cell line to deliver hIL-2 stimulates a strong immunologic cytotoxic anti-tumor response that leads to significant prolongation of survival in mice challenged with the B16/F10 intracranial melanoma tumor. Our findings demonstrate that the use of a xenogenic cell line can provide a potent vehicle for the delivery of gene therapy and may therefore represent a new approach for brain tumor therapy.     

Chromosomal aberrations and genetic relations in benign, borderline and malignant phyllodes tumors of the breast: a comparative genomic hybridization study

Phyllodes tumors are not quite rare fibroepithelial neoplasms of the breast that show a broad spectrum of clinical behaviour. The molecular genetic features of the heterogenous groups of neoplasms have not been studied in detail yet. We have used comparative genomic hybridization to analyze chromosomal copy number changes in 36 cases of phyllodes tumors (including benign, borderline and malignant phyllodes tumors, 12 cases each). The average number of chromosome copy changes (range) in benign, borderline and malignant phyllodes tumors were 5.58 (0–20), 14.08 (3–23), and 12.42 (0–29) respectively. In benign phyllodes tumors the number of gains and losses was in balance (2.50 vs 3.08), while in borderline and malignant phyllodes tumors gains occurred more often than losses (9.25 vs 4.83, 9.5 vs 2.92). The result suggests the molecular cytogenetics of borderline and malignant phyllodes tumors is similar, and the most striking difference with benign phyllodes tumors is an increased number of chromosomal gains in a nonrandom distribution. Gains of 4q12 seem especially to be involved in the progression of benign to borderline and malignant phyllodes tumors, possibly because of overexpression of oncogenes at these loci.     

大鼠肺鳞癌中p16INK4a和p19ARF基因的缺失研究

目的研究p16INK4a和p19ARF基因的缺失与大鼠肺鳞癌发生发展的关系.方法利用显微切割和聚合酶链反应(PCR)技术,在10例正常大鼠支气管黏膜上皮细胞、16例癌前病变细胞和34例肺鳞癌组织分别检测p16INK4aE1α和p19ARFE1β的缺失.结果10例大鼠正常支气管黏膜上皮细胞均未发现有p16INK4aE1α和p19ARFE1β的缺失.在16例癌前病变中发现p16INK4aE1α和p19ARFE1β缺失的检出率分别为12.50%(2/16)和6.25%(1/16);p16INK4aE1α或(和)p19ARFE1β总缺失率为18.75%(3/16).34例大鼠肺鳞癌中p16INK4aE1α和p19ARFE1β缺失的检出率分别为32.35%(11/34)和41.18%(14/34),其中有9例两者同时缺失,p16INK4aE1α或(和)p19ARFE1β总缺失率为47.06%(16/34).肺鳞癌的p19ARFE1β的缺失率显著高于癌前病变,P=0.012.结论在诱发性大鼠肺鳞癌的发生发展中,p16INK4a基因的缺失可能在早期已起作用,p19ARF的生物学活性可能强于p16INK4a.p16INK4a和p19ARF基因的同时缺失损伤了Rb和p53 2条肿瘤抑制途径,这可能有助于大鼠肺鳞癌的恶性进展.     

Promoter methylation of the TSLC1 gene in advanced lung tumors and various cancer cell lines

We previously identified TSLC1, a tumor suppressor gene in human nonsmall cell lung cancer (NSCLC). TSLC1 belongs to immunoglobulin superfamily molecules and is involved in cell adhesion. Loss of TSLC1 expression was strongly correlated with the promoter hypermethylation in several NSCLC cell lines. Here, we examined the methylation status of the TSLC1 gene promoter in 48 primary NSCLC tumors by bisulfite SSCP in combination with bisulfite sequencing. Six CpG sites around the promoter regions were significantly methylated in 21 of 48 primary NSCLC tumors (44%). Promoter methylation was more likely to be observed in relatively advanced tumors with TNM classification of pT2, pT3 or pT4 (19 of 33, 58%) than in those with pT1 (2 of 15, 13%), suggesting that alteration of TSLC1 would be involved in the progression of human NSCLC. Loss of TSLC1 expression was also observed in 20 of 46 (43%) human cancer cell lines, including those from esophageal (3 of 3), gastric (8 of 9), ovarian (2 of 5), endometrial (2 of 2), breast (1 of 3), colorectal (2 of 8) and small cell lung cancers (2 of 10). Combined analysis of promoter methylation and the allelic state in these cell lines indicated that the TSLC1 gene was often silenced not only by mono-allelic methylation associated with loss of the other allele but also through bi-allelic methylation. These results suggest that alteration of TSLC1 would be involved in advanced NSCLC as well as in many other human cancers.