Establishment and characterization of six canine hepatocellular carcinoma cell lines.

Background: Hepatocellular carcinoma (HCC) is the most common malignant liver tumor in dogs. Although surgical resection is a major treatment option for canine HCC, there are no distinct strategies for unresectable tumor subtypes or adjuvant chemotherapy for tumors with positive margins. We aimed to establish and characterize novel HCC cell lines from canine patients. Methods: The cellular morphology, general growth features and tumorigenicity of the established cell lines were evaluated. We also examined the sensitivity of the cell lines to multi-target tyrosine kinase inhibitors (TKIs). Results: We established novel canine HCC cell lines from hepatic tumors and an additional kidney tumor of six canine patients. All cell lines showed colony forming and migratory ability. KU-cHCC-001 and KU-cHCC-001-Kidney, two cell lines exhibiting high epithelial-mesenchymal transition characteristics, showed tumorigenicity in xenografted mice. Toceranib, a veterinary TKI that targets vascular endothelial growth factor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-kit, effectively inhibited the mitogen-activated protein kinase pathway and induced apoptosis. The established canine HCC cell lines showed greater sensitivity to toceranib than to sorafenib, a first-line treatment for human HCC targeting RAF/VEGFR/PDGFR. Sorafenib showed improved anti-tumor effects when co-treated with SCH772984, an extracellular signal-regulated kinase inhibitor. Conclusion: Our study suggests new therapeutic strategies for canine HCC, and these cell lines are valuable research materials for understanding HCC tumor biology in both humans and dogs.

Successful post-incomplete resection management of gastrointestinal stromal tumor using imatinib based on adenosine triphosphate-based tumor sensitivity assay in a dog.

Gastrointestinal stromal tumors arising from gastric cardia are uncommon in dogs. A few studies have shown the effectiveness of tyrosine kinase inhibitors in the treatment of canine gastrointestinal stromal tumors, but no standardized protocols are currently available. An 11-year-old spayed female Maltese dog was diagnosed with a gastrointestinal stromal tumor using histopathological and immunohistochemical analyses. An adenosine triphosphate-based tumor chemosensitivity assay revealed that imatinib at lower concentrations had a stronger inhibitory effect than toceranib. Based on the results of the assay, the dog was treated with imatinib after surgery. After 28 mo of therapy, there was no recurrence of the tumor. Key clinical message: Adenosine triphosphate-based tumor chemosensitivity assays may help clinicians to select appropriate postoperative chemotherapeutic drugs for incompletely resected gastrointestinal stromal tumors in dogs.

Gestion réussie à la suite d'une résection incomplète d'une tumeur stromale gastro-intestinale à l'aide de l'imatinib basée sur un test de sensibilité tumorale à base d'adénosine triphosphate chez un chien. Les tumeurs stromales gastro-intestinales résultant du cardia gastrique sont rares chez le chien. Quelques études ont montré l'efficacité des inhibiteurs de la tyrosine kinase dans le traitement des tumeurs stromales gastrointestinales canines, mais aucun protocole standardisé n'est actuellement disponible. Une chienne maltaise stérilisée de 11 ans a reçu un diagnostic de tumeur stromale gastro-intestinale à l'aide d'analyses histopathologiques et immunohistochimiques. Un test de chimiosensibilité tumorale à base d'adénosine triphosphate a révélé que l'imatinib à des concentrations plus faibles avait un effet inhibiteur plus fort que le tocéranib. Sur la base des résultats du test, le chien a été traité avec de l'imatinib après l'opération. Après 28 mois de traitement, il n'y a eu aucune récidive de la tumeur.Message clinique clé :Les tests de chimiosensibilité tumorale à base d'adénosine triphosphate peuvent aider les cliniciens à sélectionner les médicaments chimiothérapeutiques postopératoires appropriés pour les tumeurs stromales gastro-intestinales incomplètement réséquées chez le chien.(Traduit par Dr Serge Messier).

Case report: Adjuvant therapy with toceranib for an incompletely resected renal cell carcinoma with suspected pulmonary metastasis in a dog.

Primary renal neoplasia is rare in humans and dogs, with renal cell carcinoma (RCC) being the most common form of this cancer. As RCC is often diagnosed at an advanced stage, pulmonary metastasis is frequently observed. Tyrosine kinase inhibitors (TKIs) are the standard adjuvant treatments for metastatic RCC in humans. Similarly, in veterinary medicine, recent trials have employed TKIs for early-stage RCC patients who underwent complete surgical resection and showed no distant metastasis. However, the use of TKIs has not yet been reported commonly in cases of advanced RCC with metastasis. This case study presents the first clinical outcomes of TKI therapy in a dog with incompletely resected RCC and metastasis. A 5-year-old spayed female Chihuahua was referred to our hospital with a right renal mass and multiple pulmonary nodules suspected to be metastases. A portion of the renal mass was surgically removed, and histopathological examination revealed RCC with a high mitotic index. Adjuvant chemotherapy was administered, owing to incomplete resection with suspected pulmonary metastasis. An anticancer drug response prediction test was conducted using patient tissues. Since toceranib showed the most favorable responsiveness, it was selected as a therapeutic agent. Toceranib was orally administered at a dosage of 2.27 mg/kg every 48 h. Regular medical records for potential adverse effects were obtained, including systemic blood pressure, complete blood count, serum biochemical examination, and urinalysis. After 2 weeks of toceranib therapy, partial remission of pulmonary nodules continued for 2 months. The patient did not experience any adverse effects of the anticancer drug during the 4-month follow-up period. However, the patient died from an unidentified cause 6 months after the initial detection of the renal mass. This report describes the use of toceranib in dogs with RCC. In the present case, the patient showed an initial response to chemotherapy, and despite the presence of several poor prognostic factors, the dog survived beyond the expected 3-month lifespan to 6 months. Notably, no adverse events were observed during treatment.

Adjuvant therapy with toceranib for hepatocellular carcinoma and cholangiocarcinoma in a Pomeranian.

A 10-year-old spayed female Pomeranian dog was referred for hepatic mass evaluation. Blood tests revealed mildly elevated alkaline phosphatase activities. Computed tomography revealed a mass with multiple nodules on the right hepatic medial lobe adjacent to the caudal vena cava; histopathology confirmed mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of incomplete resection, adjuvant therapy was recommended. As tumour cells showed PDGFR-α, c-Kit, and FGFR1 overexpression, the anticancer effect of tyrosine kinase inhibitors was evaluated on the cells; toceranib was the most effective and was administered starting with an extra-labelled dose. The dog remained stable for 2.3 years with mild adverse effects. To our knowledge, this is the first successful clinical application of toceranib in a dog with mixed HCC-CC.

Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2.

We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cell migration was evaluated by monitoring wound healing. Drugs that decreased the cellular mobility of fusion-overexpressing cells compared with that of control cells were selected as candidates. Library screening revealed that erlotinib, canertinib, and lapatinib demonstrated inhibitory effects on cell migration. Activation of the EGFR signaling pathway was detected after ectopic expression of CD63-BCAR4 in normal bronchial epithelial cells, as observed by the increased phosphorylation of tyrosine residues in the EGFR protein. We also confirmed increased levels of the phosphorylated EGFR protein in resected tumors from mice injected with CD63-BCAR4 overexpressing cells. Tyrosine kinase inhibitors (TKIs) of the EGFR family significantly inhibit the migration of BCAR4 fusion-overexpressing cells and induce apoptosis at high concentrations. Among the EGFR family TKIs, canertinib, a dual EGFR/HER2 inhibitor, showed the best inhibitory effect on the migration and viability of BCAR4 fusion-overexpressing cells. We examined the effect of canertinib in vivo using a mouse xenograft model. Oral administration of canertinib to xenografted mice reduced tumor growth induced by the CD63-BCAR4 fusion gene. In addition, canertinib treatment restored E-cadherin expression and reduced the expression of epithelial-mesenchymal transition regulatory factors such as Slug and Snail. Taken together, these results suggest that EGFR/HER2 inhibitors are potential therapeutic options for BCAR4 fusion-harboring lung cancer patients, even in the absence of EGFR mutations.

Case report: Toceranib as adjuvant chemotherapy in a dog with incompletely resected combined hepatocellular-cholangiocarcinoma.

An 11-year-old intact female mixed breed dog was presented with abdominal distention and elevated hepatic enzyme levels. Computed tomography revealed a multicystic hepatic mass at the left medial lobe adjacent to the diaphragm and caudal vena cava. The mass was surgically removed with partial hepatectomy, but it could not be removed completely because of adhesion to the diaphragm. The tissue was submitted for histopathologic evaluation, and the patient was diagnosed with stage IIIA combined hepatocellular-cholangiocarcinoma (cHCC-CC). Considering the residual tumor tissue from incomplete surgical excision, adjuvant chemotherapy was recommended. Tumor tissue obtained from the patient was assessed using an anticancer drug response prediction test, and the results showed that toceranib phosphate was the most effective chemotherapeutic agent for this patient. Toceranib was initiated (3.1 mg/kg, PO, q48 h), and routine adverse effect assessment, including systemic blood pressure measurement, complete blood count, serum biochemical evaluations, and urinalysis were performed at two-week intervals for the first 2 months and every 2 months thereafter. Radiography and ultrasonography were conducted at one-month intervals for the first two months and then every 2 months subsequently. Concurrent hyperadrenocorticism was managed with trilostane (1 to 5 mg/kg, PO, q12h). The patient showed no critical adverse effects of chemotherapy, obvious recurrence, or metastasis. The response to toceranib was assessed as a partial response, and the patient is still alive over 23 months after tumor excision. This is the first case report describing chemotherapy for a dog with cHCC-CC.

Adjuvant therapy with imatinib for an incompletely resected multilobular tumour of bone in a dog.

A 5-year-old neutered male Shiba Inu dog presented with a history of oral bleeding, dysphagia, and depression for 3 weeks. The physical examination revealed a firm mass in the right caudal palatal region along the level of PM4-M2. On the computed tomography, the mass was round-to-oval in shape and 22 mm × 30 mm × 15 mm in size. The mass contained multiple bone attenuated materials with a palatal bone lysis of 4 mm × 6 mm. A complete resection of the mass was proposed; however, the owner declined due to the risk of complications associated with the radical surgery. Therefore, a palliative resection and biopsy of the mass were performed. On the histological examination, the mass was diagnosed as grade 2 multilobular tumour of bone (MTB). Since the mass was incompletely resected, adjuvant therapy was pursued along with targeted therapy using a tyrosine kinase inhibitor. The tumour cells showed overexpression of the receptor of tyrosine kinase for c-KIT, PDGFR-α, PDGFR-ß, and FGFR1 compared to normal tissue cells. Additionally, the cytotoxic effect of imatinib on the MTB cells was confirmed in vitro. Four weeks postoperatively, the administration of imatinib and carprofen was initiated and continued for 259 days. The patient maintained a good functional outcome for 306 days after the initial presentation.

Establishment of Canine Transitional Cell Carcinoma Cell Lines Harboring BRAF V595E Mutation as a Therapeutic Target.

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract and tends to have a poor prognosis due to its invasive potential. Recent studies have reported that up to 80% of canine urothelial carcinoma has the BRAF V595E mutation, which is homologous to the human V600E mutation. Activating the BRAF mutation is an actionable target for developing effective therapeutic agents inhibiting the BRAF/mitogen-activated protein kinase (MAPK) pathway in canine cancer as well as human cancer. We established novel canine TCC cell lines from two tumor tissues and one metastatic lymph node of canine TCC patients harboring the BRAF V595E mutation. Tumor tissues highly expressed the BRAF mutant and phosphorylated extracellular signal-related kinases (ERK)1/2 proteins. The derived cell lines demonstrated activated MAPK pathways. We also evaluated the cell lines for sensitivity to BRAF inhibitors. Sorafenib, a multiple kinase inhibitor targeting RAF/vascular endothelial growth factor receptor (VEGFR), successfully inhibited the BRAF/MAPK pathway and induced apoptosis. The established canine TCC cell lines responded with greater sensitivity to sorafenib than to vemurafenib, which is known as a specific BRAF inhibitor in human cancer. Our results demonstrated that canine TCC cells showed different responses compared to human cancer with the BRAF V600E mutation. These cell lines would be valuable research materials to develop therapeutic strategies for canine TCC patients.

Longitudinal assessment of B-RAF V595E levels in the peripheral cell-free tumor DNA of a 10-year-old spayed female Korean Jindo dog with unresectable metastatic urethral transitional cell carcinoma for monitoring the treatment response to a RAF inhibitor (sorafenib).

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract. In this case study, a dog with metastatic urethral TCC was treated with sorafenib. The tumor expression levels of receptor tyrosine kinase genes, including VEGFR-1, VEGFR-2, PDGFR-α, PDGFR-ß, ALK, EGFR, ErbB2, and B-RAF, were analyzed. VEGFR was overexpressed in tumor tissues compared to the normal tissues. Considering the high frequency of B-RAF mutation in canine urological tumors, the B-RAF gene was examined, and the B-RAF V595E mutation was detected in the tumor tissue. Therefore, the antitumor effect of sorafenib, a multi-tyrosine kinase inhibitor, on unresectable metastatic urethral TCC characterized by B-RAF V595E was evaluated and circulating cell-free tumor DNA (ctDNA) was assessed for monitoring the treatment response. After the initiation of oral sorafenib therapy (4 mg/kg/day escalated to 10 mg/kg/day), the dysuria was alleviated gradually, and the patient remained stable for 3 months. During that treatment period, the patient showed various levels of changes associated with B-RAF V595E mutation in ctDNA as evident from longitudinal plasma samples after initiation of sorafenib therapy. The findings of this study suggest that ctDNA may serve as a useful non-invasive tool for monitoring the treatment response to anticancer drugs.

A fusion of CD63-BCAR4 identified in lung adenocarcinoma promotes tumorigenicity and metastasis.

BACKGROUND: Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. METHODS: Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed. RESULTS: In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments. CONCLUSIONS: Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.

Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma.

Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS and ALK. This fusion gene encodes a protein comprising the N-terminal region of vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) fused to the C-terminal region of Ras-related protein 31 (Rab31). Exogenous expression of VAPA-Rab31 in immortalized normal bronchial epithelial cells demonstrated the potential transforming effects of this fusion gene, including increased colony formation and cell proliferation in vitro. Also, enhanced tumorigenicity upon VAPA-Rab31 was confirmed in vivo using a mouse xenograft model. Metastatic tumors were also detected in the liver and lungs of xenografted mice. Overexpression of VAPA-Rab31 upregulated anti-apoptotic protein Bcl-2 and phosphorylated CREB both in cells and xenograft tumors. Reduced apoptosis and increased phosphorylation of CREB and Erk were observed in VAPA-Rab31-overexpressing cells after bortezomib treatment. Elevated Bcl-2 level via activated CREB contributed to the resistance to the bortezomib-induced apoptosis. Our data suggest the oncogenic function of the novel fusion gene VAPA-Rab31 via upregulated Bcl-2 and activated CREB in lung cancer.

Galanin is an epigenetically silenced tumor suppressor gene in gastric cancer cells.

Galanin is a 30 amino-acid active neuropeptide that acts via three G-protein coupled galanin receptors, GALR1, GALR2 and GALR3. Recently, GALR1 was also suggested as a tumor suppressor gene that was frequently silenced in head and neck squamous cell carcinoma; moreover, galanin and GALR1 were reported to inhibit human oral cancer cell proliferation. However, the exact role of galanin in gastric cancer is unclear. Here, we describe the epigenetic silencing of galanin in human gastric cancer. Five gastric cancer cell lines (SNU-1, SNU-601, SNU-638, KATOIII, and AGS) showed a significant reduction in galanin expression that was restored by the demethylating agent 5-aza-2'-deoxycytidine. We confirmed the hypermethylation of CpG islands in the galanin promoter region by methylation-specific and bisulfate sequencing polymerase chain reaction (PCR). Interestingly, hypermethylated galanin did not affect galanin receptor expression. Exogenous galanin expression in silenced cells induced apoptosis and decreased phosphorylated Akt expression. Taken together, these data suggest that galanin hypermethylation impairs its tumor suppressor function in gastric cancer carcinogenesis.

Efficient Capture and Isolation of Tumor-Related Circulating Cell-Free DNA from Cancer Patients Using Electroactive Conducting Polymer Nanowire Platforms.

Circulating cell-free DNA (cfDNA) is currently recognized as a key non-invasive biomarker for cancer diagnosis and progression and therapeutic efficacy monitoring. Because cfDNA has been detected in patients with diverse types of cancers, the use of efficient strategies to isolate cfDNA not only provides valuable insights into tumour biology, but also offers the potential for developing new cancer-specific targets. However, the challenges associated with conventional cfDNA extraction methods prevent their further clinical applications. Here, we developed a nanostructured conductive polymer platform for the efficient capture and release of circulating cfDNA and demonstrated its potential clinical utility using unprocessed plasma samples from patients with breast and lung cancers. Our results confirmed that the platform's enhanced efficiency allows tumor-specific circulating cfDNA to be recovered at high yield and purity.

Mitotic cell death caused by follistatin-like 1 inhibition is associated with up-regulated Bim by inactivated Erk1/2 in human lung cancer cells.

Follistatin-like 1 (FSTL1) was identified as a novel pro-inflammatory protein showing high-level expression in rheumatoid arthritis. The protective effect of FSTL1 via the inhibition of apoptosis was reported in myocardial injury. However, the functional mechanism of FSTL1 in cancer is poorly characterized, and its proliferative effects are ambiguous. Here, we examined the effects of FSTL1 on cellular proliferation and cell cycle checkpoints in lung cancer cells. FSTL1 inhibition induced the cellular portion of G2/M phase in human lung cancer cells via the accumulation of regulators of the transition through the G2/M phase, including the cyclin-dependent kinase 1 (Cdk1)-cyclin B1 complex. An increase in histone H3 phosphorylation (at Ser10), another hallmark of mitosis, indicated that the knockdown of FSTL1 in lung cancer cells stimulated a mitotic arrest. After that, apoptosis was promoted by the activation of caspase-3 and -9. Protein level of Bim, a BH3 domain-only, pro-apoptotic member and its isoforms, BimL, BimS, and BimEL were up-regulated by FSTL1 inhibition. Degradation of Bim was blocked in FSTL1-knockdown cells by decreased phosphorylation of Bim. Increased BimEL as well as decreased phosphorylated Erk1/2 is essential for cell death by FSTL1 inhibition in NCI-H460 cells. Taken together, our results suggest that the knockdown of FSTL1 induces apoptosis through a mitotic arrest and caspase-dependent cell death. FSTL1 plays the important roles in cellular proliferation and apoptosis in lung cancer cells, and thus can be a new target for lung cancer treatment.

Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer.

OBJECTIVE: Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. METHODS: We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. RESULTS: After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. CONCLUSIONS: Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC.

Direct patterning and biofunctionalization of a large-area pristine graphene sheet.

Direct patterning of streptavidin and NIH 3T3 fibroblast cells was successfully achieved over a large-area pristine graphene sheet on Si/SiO2 by aryl azide-based photografting with the conventional UV lithographic technique and surface-initiated, atom transfer radical polymerization of oligo(ethylene glycol) methacrylate.

Mussel-inspired, perfluorinated polydopamine for self-cleaning coating on various substrates.

We designed a perfluorinated dopamine derivative, which, upon oxidative polymerization, formed a structurally rough film of extremely low surface energy on various substrates. The static water contact angles larger than 150° and the low water sliding angles less than 7° confirmed the formation of superhydrophobic, self-cleaning surfaces.

Generation of cellular micropatterns on a single-layered graphene film.

Micropatterns of fibroblast and hippocampal neurons are generated on a single-layered graphene substrate. A large-area (1 cm × 1 cm) graphene film on Si/SiO2 is functionalized by surface-initiated ATRP of non-biofouling oligo(ethylene glycol) methacrylate, after grafting of the polymerization initiator bearing α-bromoisobutylate via photoreaction of the perfluorophenyl azide group. The microcontact printing-assisted spatio-selective reaction, after chemical activation of the terminal hydroxyl group of oligo(ethylene glycol) in the polymeric film, is utilized to generate the patterns of fibroblast and hippocampal neurons.

Genetic variations associated with postoperative recurrence in stage I non-small cell lung cancer.

PURPOSE: Postoperative recurrence in stage I non-small cell lung cancer (NSCLC) is the major cause of a poor prognosis. This study aims to identify genetic variants that are associated with the prognosis of early-stage NSCLCs. EXPERIMENTAL DESIGN: A genome-wide association study (GWAS) was conducted in 250 patients in stage I NSCLCs and the results were replicated in additional 308 patients. RESULTS: Results from an Affymetrix Genome-wide Human SNP array in 250 patients identified 94 SNPs with significant associations (P < 2 × 10(-4)), which were selected for replication in 308 additional patients. Pooled analysis of the 558 patients determined that rs1454694 in chromosome 4q34 was the most significant marker of lung cancer prognosis in the stage I patients (adjusted HR = 2.81; P = 5.91 × 10(-8)). After the candidate loci were mapped, an additional four markers at chromosome 4q34.3 were significantly associated with recurrence-free survival (RFS; P < 5 × 10(-5)). A haplotype of five SNPs in 4q34 also showed significant association with RFS (P = 4.29 × 10(-6)). CONCLUSIONS: A genetic polymorphism rs1454694 was identified as a novel genetic risk factor for RFS of stage I NSCLCs. This genome-wide study suggests that genetic markers in 4q34.3 contribute to predict the prognosis of Korean patients with stage I NSCLCs.

Prognostic implications of genetic variants in advanced non-small cell lung cancer: a genome-wide association study.

The prognostic significance of inherited genetic variants in advanced-stage non-small cell lung cancer (NSCLC) patients remains unknown. In this study, we genotyped 271 817 single-nucleotide polymorphisms in 348 advanced NSCLC patients who received chemotherapy and analyzed their association with prognosis by using Cox proportional hazard regression model adjusted for known prognostic factors. Top candidate single-nucleotide polymorphisms (SNPs) were selected using the bootstrap re-sampling procedure. Median age of patient population was 56 years. Proportions of female, never smokers and adenocarcinoma were 64.9, 67.5 and 80.4%, respectively. We identified 17 top candidate SNPs related to prognosis using cut-off minimum P value of <5.0 × 10(-5) in at least 70% of 1000 bootstrap samples. These SNPs were located in the genomic regions of the FAM154A, ANKS1A, DLST, THSD7B, NCOA2, CDH8, SLC35D2, NALCN and EGF genes. The most significant SNP, rs1571228 (9p22.1:FAM154A), was significantly associated with overall survival in dominant model [AG+GG to AA, hazard ratio (HR) of death (95% CI) = 0.53 (0.42-0.67); P = 2.025 × 10(-7)]. The SNP at 4q25:EGF, rs11098063, for which some genetic variations was previously reported to be associated with prognosis, also showed significant association with overall survival in additive model [CC versus CT versus TT, HR (95% CI) = 1.00 versus 0.61 (0.47-0.78) versus 0.39 (0.19-0.79); P = 9.582 × 10(-6)]. Survival differences according to the genotype of these SNPs were independent of sex, smoking, histology and chemotherapy regimens. These results suggested the variants at multiple genetic loci might contribute to the risk of death in advanced NSCLC patients receiving chemotherapy.