RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis.

BACKGROUND: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors. METHODS: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement. RESULTS: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001). CONCLUSIONS: The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.

Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations.

BACKGROUND: Recently, driver tyrosine kinase gene mutations have been detected in malignant tumors, including lung tumors. Notwithstanding their attractiveness as targets for molecular therapy, limited information is available regarding BRAF-mutated lung carcinomas. MATERIALS AND METHODS: BRAF mutation status was determined in 2001 surgically resected nonsmall-cell lung cancer (NSCLC) cases using high-resolution melting analysis (HRMA) followed by Sanger sequencing and/or deep sequencing using next generation sequencer. RESULTS: BRAF mutations were detected in 26 (1.3%) of 2001 NSCLC cases (25 adenocarcinomas and 1 squamous cell carcinoma). In the 26 cases, 13 mutation genotypes were identified, including V600E (8 of 26; 30.8%), G469A (6 of 26; 23.1%), K601E (4 of 26; 15.4%), and other residual mutations (1 of 26; 0.04%). Of the 13 genotypes, 4 genotypes (G464E, G596R, A598T, and G606R) had not been previously reported in lung cancer. The overall survival rate was not significantly different between patients with wild-type BRAF and those with V600E or non-V600E BRAF mutations (P = 0.49 and P = 0.15, respectively). Histomorphological analysis revealed that focal clear cell changes were present in 75% of V600E-mutated tumors. All V600E BRAF-mutated tumors were negative for other driver gene alterations including epidermal growth factor receptor (EGFR) and KRAS mutations and the anaplastic lymphoma kinase gene translocation, whereas five tumors with non-V600E BRAF mutations (four G469A and one G464E/G466R) showed concomitant EGFR mutations. CONCLUSION: The frequency of BRAF mutations in lung cancer was low in an Asian cohort. Furthermore, BRAF mutation status lacked prognostic significance in this patient population.

Human microRNA hsa-miR-1231 suppresses hepatitis B virus replication by targeting core mRNA.

Pathogen-specific miRNA profiles might reveal potential new avenues for therapy. To identify miRNAs directly associated with hepatitis B virus (HBV) in hepatocytes, we performed a miRNA array analysis using urokinase-type plasminogen activator (uPA)-severe combined immunodeficiency (SCID) mice where the livers were highly repopulated with human hepatocytes and human immune cells are absent. Mice were inoculated with HBV-infected patient serum samples. Eight weeks after HBV infection, human hepatocytes were collected from liver tissues, and miRNAs were analysed using the Toray 3D array system. The effect of miRNAs on HBV replication was analysed using HBV-transfected HepG2 cells. Four miRNAs, hsa-miR-486-3p, hsa-miR-1908, hsa-miR-675 and hsa-miR-1231 were upregulated in mouse and human livers with HBV infection. These miRNAs were associated with immune response pathways such as inflammation mediated by chemokine and cytokine signalling. Of these miRNAs, hsa-miR-1231, which showed high homology with HBV core and HBx sequences, was most highly upregulated. In HBV-transfected HepG2 cells, overexpression of hsa-miR-1231 resulted in suppression of HBV replication with HBV core reduction. In conclusion, a novel interaction between hsa-miR-1231 and HBV replication was identified. This interaction might be useful in developing new therapeutic strategies against HBV.

The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Changes of SM muscles after STG harvest.

Semimembranosus (SM) muscle as well as Semitendinosus-Gracilis (STG) tendon have the same role in knee flexion and tibial internal rotation. Because STG tendons are generally used for anterior cruciate ligament (ACL) reconstruction, some compensational changes in SM muscle might have been induced. The purpose of this study was to investigate the changes of SM muscle affected by harvesting STG tendons. 10 Wistar-strain male rats were divided into control (C) and STG-dissected (STG) groups. Left STG tendons including the distal half of muscle portions were dissected in group STG and only skin incision was performed in group C. 4 weeks after the treatments, fiber types classification and ultrastructural observations were performed. In group STG the decrease of type IIa (fast-twitch fiber with high oxidative capacity) was observed in deep layers of SM muscle (p<0.01). In ultrastructural observations, the increase in lipid droplets and mitochondria and the irregularity of Z disc were observed in deep layers. These morphological changes indicated that the mechanical loading might increase in SM muscle after harvesting of STG. Because of minor injuries in SM muscle, hamstring strength exercise at early stage of rehabilitation program should be carefully performed following ACL reconstruction using STG tendons in clinical practice.

Accelerated sliding of pollen tube organelles along Characeae actin bundles regulated by Ca2+.

Pollen tubes show active cytoplasmic streaming. We isolated organelles from pollen tubes and tested their ability to slide along actin bundles in characean cell models. Here, we show that sliding of organelles was ATP-dependent and that motility was lost after N-ethylmaleimide or heat treatment of organelles. On the other hand, cytoplasmic streaming in pollen tube was inhibited by either N-ethylmaleimide or heat treatment. These results strongly indicate that cytoplasmic streaming in pollen tubes is supported by the "actomyosin"-ATP system. The velocity of organelle movement along characean actin bundles was much higher than that of the native streaming in pollen tubes. We suggested that pollen tube "myosin" has a capacity to move at a velocity of the same order of magnitude as that of characean myosin. Moreover, the motility was high at Ca2+ concentrations lower than 0.18 microM (pCa 6.8) but was inhibited at concentration higher than 4.5 microM (pCa 5.4). In conclusion, cytoplasmic streaming in pollen tubes is suggested to be regulated by Ca2+ through "myosin" inactivation.

Externally suppressible proline quadruplet ccc U.

Three (+1) frameshift mutations located at different genetic sites respond with high specificity to the same external suppressor. In each case, the suppressor restores small amounts of protein that is normal in electrophoretic mobility and heat stability. One of these proteins has been shown to have the wildtype amino acid sequence. The messenger RNA quadruplet CCCUappears to be common to all three frameshift sites and to be translated by the suppressor as proline. A likely suppressor agent is a proline transfer RNA with a quadruplet anticodon or its functional equivalent.

[Which tube is better for esophagectomy?].

We performed differential lung ventilation for thoracoscopic esophagectomy. There are 2 tools available for differential lung ventilation: double lumen tube (DLT) and endbronchial blocker tube (blocker). We reviewed the best tube by studying esophageal cancer perioperative findings in thoracoscopic esophagectomy. We examined 85 esophagectomy cases from 2007, in which we used a blocker combined with a spiral tracheal tube or DLT. An average of 1.5 times displacement of the blocker occurred in blocker cases and resulted in ventilation inability requiring a surgical interruption. Because bronchial displacement was present, 2 cases had to block it in an intermediate bronchial trunk. In DLT cases, tube movement was not seen and we could maintain good ventilation. However, lymph node dissection (LND) was difficult in DLT cases and DLT required exchange via a spiral tube for cervical LND. Next, we compared 4 DLTs, and found that the phi con DLT tube was the best because of its pliability. We concluded that the best tube for esophagectomy is a phi con DLT because it allows easy control of the differential lung ventilation and this tube does not interfere with surgery.

Prevalence and specificity of LKB1 genetic alterations in lung cancers.

Germline LKB1 mutations cause Peutz-Jeghers syndrome, a hereditary disorder that predisposes to gastrointestinal hamartomatous polyposis and several types of malignant tumors. Somatic LKB1 alterations are rare in sporadic cancers, however, a few reports showed the presence of somatic alterations in a considerable fraction of lung cancers. To determine the prevalence and the specificity of LKB1 alterations in lung cancers, we examined a large number of lung cancer cell lines and lung adenocarcinoma (AdC) specimens for the alterations. LKB1 genetic alterations were frequently detected in the cell lines (21/70, 30%), especially in non-small cell lung cancers (NSCLCs) (20/51, 39%), and were significantly more frequent in cell lines with KRAS mutations. Point mutations were detected only in AdCs and large cell carcinomas, whereas homozygous deletions were detected in all histological types of lung cancer. Among lung AdC specimens, LKB1 mutations were found in seven (8%) of 91 male smokers but in none of 64 females and/or nonsmokers, and were significantly more frequent in poorly differentiated tumors. The difference in the frequency of LKB1 alterations between cell lines and tumor specimens was likely to be owing to masking of deletions by the contamination of noncancerous cells in the tumor specimens. These results indicate that somatic LKB1 genetic alterations preferentially occur in a subset of poorly differentiated lung AdCs that appear to correlate with smoking males.

Spontaneous hyperactivity in mutant mice lacking the NMDA receptor GluRepsilon1 subunit is aggravated during exposure to 0.1 MAC sevoflurane and is preserved after emergence from sevoflurane anaesthesia.

BACKGROUND AND OBJECTIVE: Patients who awake from sevoflurane anaesthesia with symptoms of agitation may have some underlying functional substrate that is sensitive to the low concentrations of anaesthetic encountered during emergence. One candidate for such a substrate could be neurocircuitry implied in the pathophysiology of both agitation and movement disorders with hyperactivity. We postulated that hyperactive animals would show a further increase in activity in the presence of low concentrations of volatile anaesthetics, such as sevoflurane. METHODS: To confirm our hypothesis, we examined the effects of two subanaesthetic concentrations of sevoflurane, isoflurane and halothane (0.1 and 0.2 MAC (minimum alveolar concentration)) on spontaneous activity in N-methyl-d-aspartate receptor GluRepsilon1 subunit knockout mice exhibiting locomotor hyperactivity in a novel environment and compared these results with those for wild-type controls. We also compared the effects of anaesthetic concentrations of sevoflurane (1.2 MAC) on mice activity during postanaesthesia recovery. RESULTS: Out of the three anaesthetics used, only sevoflurane administered at 0.1 MAC caused a significantly different response between the two experimental groups. Exposure to this subanaesthetic concentration of sevoflurane reduced the activity of wild-type mice, whereas mutant animals showed a further increase in hyperactivity. The effects of 1.2 MAC sevoflurane anaesthesia on mice activity during postanaesthesia recovery also differed significantly between the two genotypes. Exposure to anaesthetic concentrations of sevoflurane had a sedative effect on wild-type mice, whereas mutant mice preserved their high levels of activity upon emergence from the anaesthesia. CONCLUSIONS: The presence of an inherent anomaly in mutant mice that becomes more manifest during exposure to 0.1 MAC sevoflurane and is still present after the emergence from sevoflurane anaesthesia suggests the presence of and necessitates a search for some putative substrate that may, by analogy, underlie emergence agitation in the clinical setting.

[Risk and its management in video-assisted thoracic surgery].

To avoid intraoperative accidents or trouble with patients in video-assisted thoracic surgery (VATS), the surgeons should complete sufficient training. Patients tend to have excessive expectation for less invasive approach, proper information of VATS procedure must be given to the patients as well as the referring physicians. Sufficient cancer surgery should be considered prior to applying VATS approach. If cancer recurred after VATS operation, it is far from minimally invasive surgery. The lung and the pulmonary artery are very fragile. Surgeons who are performing VATS surgery must have a skill of suturing the lung and some bleeding control technique. These well trained technique and the ability of judge will manage the risk and the accident in VATS operations.

Identification of tumor markers and differentiation markers for molecular diagnosis of lung adenocarcinoma.

To identify tumor markers and differentiation markers for lung adenocarcinoma (AdC), we analysed expression profiles of 14,500 genes against three cases of type II alveolar epithelial cells, bronchiolar epithelial cells, and bronchial epithelial cells, respectively, and 10 cases of AdC cells isolated by laser capture microdissection. Hierarchical clustering analysis indicated that AdC cells and noncancerous lung epithelial cells are significantly different in their expression profiles, and that different sets of differentiation markers are expressed among alveolar, bronchiolar and bronchial epithelial cells. Nine genes were identified as being highly expressed in AdC cells, but not expressed in noncancerous lung epithelial cells. Sixteen genes were identified as differentiation markers for lung epithelial cells. Real-time RT-PCR analysis of 45 lung AdC cases further revealed that expression of four tumor markers in AdC cells was significantly higher than that in noncancerous lung cells and that expression of ten differentiation markers was retained in a considerable fraction of lung AdC cases. Five tumor markers and seven differentiation markers were not expressed in peripheral blood cells. Similarities and differences in expression profiles between normal epithelial cells from different lung respiratory compartments and AdC cells demonstrated in this study will be informative for the molecular diagnosis of lung AdC.

[Collapse of the contra-lateral lung after computed tomography-guided marking].

We are performing preoperative percutaneous computed tomography (CT)-guided placement of hook-wires to localize small lesions on the day before thoracoscopic surgery. We report a case of collapse of the contra-lateral lung after CT-guided marking. A 69-year-old man was referred to our department for surgical intervention of multiple small lung tumors in the right upper lobe. At the age of 66, he underwent esophagectomy for esophageal cancer. CT-guided marking was undergone for both tumors on the day before surgery. After marking, collapse of the contra-lateral (left) lung was occurred. Left chest tube was placed in order to maintain adequate ventilation during the operation. Operative findings revealed that sealing test after resections of the lung could not be performed because the fistel to the left chest cavity at the inferior mediastinum after esophagectomy was detected.

Structures of the extracellular domain of the type I tumor necrosis factor receptor.

BACKGROUND: Tumor necrosis factor (TNF) is a powerful cytokine that is involved in immune and pro-inflammatory responses. Two TNF receptors that belong to the cysteine-rich low affinity nerve growth factor receptor family (TNF-R1 and TNF-R2) are the sole mediators of TNF signalling. Signalling is thought to occur when a trimer of TNF binds to the extracellular domains of two or three receptor molecules, which permits aggregation and activation of the cytoplasmic domains. The complex is then internalized within an endocytic vesicle, whereupon it dissociates at low pH. Structure of the soluble extracellular domain of the receptor (sTNF-R1) both in the unliganded and TNF-bound state have previously been determined. In both instances, the fourth subdomain of the receptor was found to be partly disordered. In the unliganded state at pH 7.5, the extracellular domain forms two distinct types of dimer, parallel and antiparallel; the antiparallel dimer occludes the TNF-binding. RESULTS: We have determined the structure of sTNF-R1 in two crystal forms in high salt at pH 3.7. The orthorhombic crystals diffract to 1.85 ånd the entire polypeptide is well ordered. In contrast, the C-terminal 32 residues are disordered in the hexagonal crystals. In the orthorhombic form, these residues exhibit a topology and disulphide connectivity that differs from the other three cysteine-rich domains in the molecule. In both forms, the interface is considerably more extensive than that used in complex formation with LTalpha. This 'low pH' dimer is different from both of the dimers observed in crystals grown at pH 7.5. CONCLUSIONS: The occurrence of the antiparallel dimers in both low pH crystal forms suggest that they are not an artefact of crystal packing. Such dimers may form in the low pH environment of the endosome. Because the dimer contact surface occludes the TNF-binding site, formation of this dimer would dissociate the TNF-receptor complex within the endosome. Three of the four cysteine-rich domains of TNF-R1 are constructed from two distinct structural modules, termed A1 and B2. The fourth subdomain comprises an A1 module followed by an unusual C2 module. Although the orientation of these modules with respect to each other is sensitive to crystal packing, ligand binding, pH and ionic strength, the modules are structurally well conserved between and within the known sTNF-R1 structures.

Clinicopathological significance of Fhit protein expression in stage I non-small cell lung carcinoma.

Abnormalities in structure and expression of the FHIT gene have been detected in a considerable fraction of primary lung tumors. Previous reports indicated that FHIT gene alterations can be simply detected by immunohistochemical methods. Therefore, we investigated the association of Fhit expression with clinicopathological features and allelic imbalance (AI) at the FHIT locus in 105 stage I non-small cell lung cancers (NSCLC) by the immunohistological method and PCR analysis. Thirty-six of 105 (34%) tumors showed marked reduction of Fhit immunoreactivity. Fhit expression was markedly reduced in most squamous cell carcinomas (24 of 28, 86%), whereas such a reduction was detected only in a small subset of adenocarcinomas (7 of 67, 10%; P < 0.001). A marked reduction of Fhit protein expression was observed more frequently in patients with a smoking history (32 of 80, 40%) than in patients without a smoking history (4 of 25, 16%; P = 0.013). These results indicate that FHIT gene alterations preferentially occur in squamous cell carcinomas and in smokers. Furthermore, a reduction of Fhit protein expression in tumor cells was associated with a poorer survival of patients with stage I NSCLC, irrespective of histological subtypes of tumors (P = 0.005; log-rank test). Fhit expression was reduced preferentially in tumors with AI at the FHIT locus; however, AI at the FHIT locus did not correlate with patients' survival (P = 0.262; log-rank test). These results suggested that Fhit protein expression could be a useful molecular marker for the prognosis of patients with surgically resected stage I NSCLC.

Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma.

Although it is widely accepted that tumor suppressor genes play an important role in the genesis and progression of human cancer, little is known about genetic events that accumulate during multistage lung carcinogenesis. Thus, to determine a subset of tumor suppressor genes that are involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), 22 brain metastases and 23 stage I primary lung tumors were examined for allelic losses at 40 loci on 10 chromosomes including the loci of 5 tumor suppressor genes, APC, WT1, RB, p53, and DCC. The incidence of allelic losses on chromosomes 3p, 13q, and 17p was high (> 60%) in both primary tumors and brain metastases. In brain metastases, a high incidence of allelic losses (> 60%) was also observed at loci on chromosomes 2q, 18q, and 22q, and the incidence of allelic losses on these chromosomes in brain metastases was significantly higher than that in primary tumors (P < 0.05). In two cases of brain metastases with corresponding primary lung tumors, sequential accumulation of allelic losses during progression of primary lung tumors was observed on several chromosomes including chromosomes 2q and 18q. These results indicate that, besides loss of heterozygosity for chromosomes 3p, 13q, and 17p, loss of heterozygosity for chromosomes 2q, 18q, and 22q also occurs frequently in advanced NSCLCS. Thus, it is possible that loss of heterozygosity on chromosomes 2q, 18q, and 22q occurs late in the progression of NSCLC and/or causes phenotypic alterations of NSCLC cells into more aggressive ones.

Alterations of the PPP1R3 gene in human cancer.

Recently, the PTEN/MMAC1 gene encoding a protein phosphatase (PP) and the PPP2R1B gene encoding a regulatory subunit of PP2A have been identified as being genetically altered in several types of human cancers, indicating that aberrations of intracellular signaling pathways via PPs are involved in human carcinogenesis. Here we report genetic alterations of the PPP1R3 gene located at chromosome 7q31, which encodes regulatory subunit 3 of PP1, in various types of human cancers. Mutations of the PPP1R3 gene were detected in 5 of 33 (15%) non-small cell lung cancer cell lines and 2 of 38 (5%) primary non-small cell lung cancers and were also observed in cell lines derived from a small cell lung cancer, an ovarian cancer, a colorectal cancer, and a gastric cancer. Mutations were widely dispersed in the coding region of the PPP1R3 gene. Three of the 11 detected mutations were nonsense mutations, whereas the remaining ones were missense mutations, most of which caused substitutions of evolutionarily conserved amino acids. These findings suggest that PPP1R3 alteration plays a role in the development of human cancers and that PPP1R3 could act as a tumor suppressor gene.

Deletion map of chromosome 9 and p16 (CDKN2A) gene alterations in neuroblastoma.

We reported previously that loss of heterozygosity (LOH) on chromosomes 2q, 9p and 18q frequently occurs in neuroblastoma and that patients with 9p LOH in the tumors showed statistically significant association with an advanced stage of the disease and poor prognosis. To determine the role of chromosome 9 loss in neuroblastoma, we performed deletion mapping of chromosome 9 in 80 cases of neuroblastoma using 11 polymorphic microsatellite markers and a restriction fragment length porymorphism marker. LOH at one or more loci on chromosome 9 was detected in 33 of 80 cases (41%). Chromosome 9p was lost in 24 of 80 cases (32%), whereas chromosome 9q was lost in 18 of 80 cases (23%). There were two commonly deleted regions mapped to 9p21 between the D9S171 marker and the IFNB1 marker and 9q34-qter distal to the D9S176 marker. In addition, patients with LOH at 9p21 but not at 9q34-qter in the tumors showed statistically significant association with poor prognosis (P = 0.023). Because the commonly deleted regions at 9p21 includes the p16 (CDKN2A) gene, the status of the p16 gene was further examined in 80 fresh tumors and 19 cell lines of neuroblastoma. A missense mutation was detected at codon 52 in a fresh tumor. The p16 gene was not expressed in 13 of 19 cell lines (72%), and 5 of the 13 cell lines displayed methylation of the CpG island surrounding the first exon of the p16 gene. These results suggest that the p16 gene is a candidate tumor suppressor gene for neuroblastoma, and its inactivation may contribute to the progression of neuroblastoma.

A novel tumor suppressor locus on chromosome 18q involved in the development of human lung cancer.

The high incidence of loss of heterozygosity (LOH) on chromosome 18q in advanced non-small cell lung carcinomas indicates the presence of tumor suppressor gene(s) on this chromosome arm, which plays an important role in the acquisition of malignant phenotypes in lung cancers. In the present study, we examined 62 lung cancer specimens and 54 lung cancer cell lines for allelic imbalance at 11 microsatellite loci to define common regions of 18q deletions. Allelic imbalance of 18q was detected in 24 (55.8%) non-small cell lung carcinoma specimens and in 6 (31.6%) small cell lung carcinoma specimens, whereas a similar frequency of LOH was statistically inferred to occur in cell lines by analyzing marker homozygosity as an indirect measure of LOH. Five specimens and 11 cell lines showed partial or interstitial deletions of chromosome 18q, and 2 of them had homozygous deletions at the 18q21.1 region. A commonly deleted region was assigned between the D18S46 and y953G12R loci. The size of this region is less than 1 Mb, and the coding exons of three candidate tumor suppressor genes, Smad2, Smad4, and DCC, were mapped outside the region. This result suggests that the common region harbors a novel tumor suppressor gene involved in the progression of lung cancer.