An extremely rare case of small-cell lung cancer harboring variant 2 of the EML4-ALK fusion gene

Anaplastic lymphoma kinase (ALK) fuses echinoderm microtubule-associated protein-like 4 (EML4) to acquire a transforming activity in lung adenocarcinomas. However, the presence of an EML4-ALK fusion gene in other lung cancer histologies is an extremely rare phenomenon. A 43-year-old female was referred to our department due to dyspnea on effort and left back pain. Computed tomography (CT) showed a large mass in the upper lobe of the left lung and a massive left pleural effusion, while a CT-guided needle biopsy confirmed a diagnosis of small-cell lung cancer (SCLC). Surprisingly, the tumor was genetically considered to harbor the EML4-ALK fusion gene (variant 2). Although the patient underwent two regimens of cytotoxic chemotherapy for SCLC, she died approximately seven months after the administration of first-line chemotherapy. Our analysis of 30 consecutive patients with SCLC for EML4-ALK revealed that two patients, including the current patient and a patient we previously reported, harbored the EML4-ALK fusion gene.     

Temsirolimus therapy in a patient with lung adenocarcinoma harboring an FBXW7 mutation

We report the identification of an FBXW7 mutation in a patient with adenocarcinoma of the lung, whose tumor had previously been shown to be EGFR and ALK wild type and who had previously progressed on multiple lines of systemic therapy. She experienced both clinical and radiographic benefit from treatment with the mTOR inhibitor temsirolimus.     

Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer

Fibroblast growth factor receptor 1 (FGFR1) is an oncogene that can potentially be targeted by tyrosine kinase inhibitors. We aimed to investigate the prevalence and prognostic significance of alterations in FGFR1 copy number in non-small cell lung cancer (NSCLC). FGFR1 status was evaluated by chromogenic silver in situ hybridisation (ISH) in tissue microarray sections from a retrospective cohort of 304 surgically resected NSCLCs and results were correlated with the clinicopathological features and overall survival. High FGFR1 gene copy number (amplification or high-level polysomy) was significantly more frequent in squamous cell carcinomas (SCC) (24.8%) and large cell carcinomas (LCC) (25%) compared to adenocarcinomas (11.3%) (p = 0.01 and p = 0.03 respectively). Among NSCLC there was no significant correlation between FGFR1-positive status and other clinicopathological features including age, gender, smoking history, tumour size, lymph node status, stage, grade, vascular, lymphatic or perineural invasion. FGFR1-positive patients showed a tendency to longer overall survival in univariate analysis (p = 0.14). Multivariate survival analysis using Cox regression model confirmed FGFR1-positive patients had a significant reduction in the risk of death compared to FGFR1-negative patients (HR 0.6; p = 0.02). High FGFR1 gene copy number is a common finding in SCC and LCC and is an independent favourable prognostic factor.     

A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer

Exposure to tobacco smoke as well as environmental and occupational factors is the major cause of lung cancer. Non-small cell lung cancer (NSCLC) is the major histological type. Genes in pathways affecting inflammation, cellular stress and apoptosis are important, and the extent of inflammation in the lung could be affected by polymorphisms modifying these responses. In the present study we have investigated whether a combination of potential functional polymorphisms in genes related to inflammation may modulate risk of NSCLC. Eleven functional polymorphisms in nine genes were analyzed for association with risk of NSCLC in 882 subjects from the Norwegian population. The results showed that individuals carrying combination of three functional polymorphisms in the caspase-8, matrix metalloproteinase-1, seleno-protein S1, and interleukin-10 genes had two-fold increased risk of NSCLC (OR 2.06 (95% CI, 1.19-3.47) whereas individuals with four risk genotypes had 4.62-fold increased risk (OR 4.62, 95% CI, 1.69-12.63). These results highlight the need to investigate the combinatory effects of multiple SNPs in the carcinogenesis of the lung.     

XRCC1 polymorphisms and lung cancer risk in Chinese populations: A meta-analysis

X-ray repair cross-complementing group 1 (XRCC1), one of the >20 genes that participate in the base excision repair (BER) pathway, is thought to account for differences in lung cancer susceptibility. Our meta-analysis on 2861 cases (lung cancer patients) and 2783 controls from eight eligible studies in Chinese populations showed that for the XRCC1 Arg194Trp polymorphism, compared with the Arg/Arg homozygous genotype, the variant Arg/Trp and Trp/Trp genotypes combined was not associated with lung cancer risk (OR = 1.06, 95% confidence interval [CI] = 0.89–1.27) (Z = 0.70, P = 0.48), nor was Arg280His (OR = 0.63, 95% CI = 0.28–1.41) (Z = 1.12, P = 0.26); however, for the XRCC1 Arg399Gln polymorphism, the combination of variant Arg/Gln and Gln/Gln genotypes was borderline significantly associated with lung cancer risk (OR = 1.16, 95% CI = 1.00–1.36) (Z = 1.90, P = 0.06), compared with the Arg/Arg homozygous genotype. Therefore, in the eight published studies in Chinese populations, we found little evidence of an association between the combined variant genotypes of the XRCC1 Arg399Gln polymorphism and the increased risk of lung cancer.     

Prediction for response duration to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutated never smoker lung adenocarcinoma

Objectives

Among non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations, ∼20–30% exhibit de novo resistance to EGFR-tyrosine kinase inhibitor (TKI). The aim of this study was to examine whether mutations in the EGFR-downstream genes may be associated with de novo resistance to EGFR-TKIs in EGFR mutation-positive patients.

Materials and methods

Sixty-eight never-smoker adenocarcinoma patients with an activating EGFR mutation were included in the mutational analysis and 55 patients treated with EGFR-TKIs were analyzed for the treatment outcomes to EGFR-TKIs. We concurrently analyzed mutations in PIK3CA, PTEN, AKT and STK11, which are all EGFR-downstream genes. Mutations in PIK3CA, PTEN, AKT, and STK11 were analyzed by polymerase chain reaction-based sequencing.

Results

PIK3CA mutations were detected in 4.4% (3/68) of patients, PTEN mutations in 16.1% (11/68), AKT mutations in 5.9% (4/68), and STK11 mutations in 13.2% (9/68). One patient with an activating exon 21 L858R mutation concomitantly had an exon 20 T790M mutation in EGFR. The proportion of patients who had mutations in EGFR-downstream genes was 32.4% (22/68). When we analyzed the treatment outcome of 55 patients treated with EGFR-TKI, the presence of mutations in EGFR-downstream genes correlated with a poor overall response rate to EGFR-TKIs (63.6 vs.14.5% in patients with mutation in EGFR-downstream gene, P < 0.0001), shorter median progression-free survival (12.0 vs. 3.0 months, P = 0.060), and shorter median overall survival (18.9 vs. 25.0 months, P = 0.048).

Conclusion

Mutations in the EGFR-downstream genes may confer resistance to EGFR-TKIs and result in poor treatment outcomes in never-smoker adenocarcinoma patients with activating EGFR mutations.     

MLL partner genes in secondary acute lymphoblastic leukemia: Report of a new partner PRRC1 and review of the literature

Secondary acute lymphoblastic leukemia (sALL) following chemotherapy and/or radiotherapy of previous malignancies represents 2–10% of all cases of ALL. A 72-year-old female patient was diagnosed with acute lymphoblastic leukemia following chemotherapy for a diffuse large B cell lymphoma. Banding cytogenetics showed a t(t(5;11)(q23–31;q23) in 20 of the 21 metaphases examined and fluorescent in situ hybridization confirmed rearrangement of MLL. Long distance inverse-polymerase chain reaction revealed an in-frame fusion between 5′MLL and 3′PRRC1. Sixty-five cases of sALL associated with 11q23/MLL rearrangement, including 47 with a t(4;11)(q21;q23), were retrieved from the literature. Drug regimen used to treat the primary neoplasm was available for 54 patients; 52 had received a topoisomerase II inhibitor, known to induce MLL rearrangement.     

Enhanced antitumor effects by combination gene therapy using MDR1 gene shRNA and HSV1-tk in a xenograft mouse model

The use of a novel therapeutic vector containing HSV1-thymidine kinase (HSV1-tk) and a short hairpin RNA for the MDR1 gene (shMDR) was proposed previously. We investigated the antitumor effects in an in vivo mouse model of colon cancer and assessed treatment response by serial non-invasive imaging. shMDR-TK expressing (MTKG) tumors for the dual therapy group mice with ganciclovir and doxorubicin showed a decrease in size, while tumors in the single therapy group mice showed a moderate increase (p < 0.05). The ¹³¹I-5-iodo-2′-fluoro-2′deoxy-1-β-d-arabinofuranosyluracil (FIAU) uptake ratio of MTKG-to-parent HCT-15 tumors decreased as treatment progressed for single or dual therapy group mice, while that of the control group mice increased gradually. This study demonstrates the enhanced antitumor effects with combination gene therapy compared with a single therapeutic approach, and provides the potential of therapeutic response monitoring.     

A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis

The incidence of most solid tumors is remarkably reduced in individuals with Down syndrome. Using mouse models of Down syndrome, we have previously shown that this decrease in tumor incidence is due, in part, to suppression of tumor angiogenesis as a consequence of attenuated calcineurin signaling in endothelial cells. Our prior studies utilized xenografted tumors in a transgenic mouse model with three copies of the Down syndrome critical region-1 (Dscr1) gene, a chromosome 21-encoded endogenous calcineurin inhibitor. These data indicate that upregulated Dscr1 contributes to broad cancer protection by suppressing tumor angiogenesis through inhibiting the calcineurin pathway in the vascular endothelium. However, it still remains to be confirmed whether a single extra copy of Dscr1 is also sufficient to suppress tumor angiogenesis in slow growing spontaneous tumors that more accurately recapitulate molecular features of human malignancies. In this study, utilizing LSL-Kras^G12D mice, an inducible and autochthonous model of human lung adenocarcinoma, on a Dscr1 transgenic mouse background, we show that a single extra transgenic copy of Dscr1 provides a survival advantage in these mice developing spontaneous lung tumors driven by oncogenic Kras^G12D without affecting either initiation or progression of spontaneous lung tumors. Furthermore, we show that Dscr1 trisomy significantly reduces microvessel density in lung tumors and thus limits the growth of lung tumors through decreased proliferation and increased apoptosis of lung tumor cells. These data provide evidence that a single extra copy of Dscr1 is sufficient to suppress tumor angiogenesis during spontaneous lung tumorigenesis and further support our hypothesis that suppression of tumor angiogenesis by an additional copy of Dscr1 contributes to the reduced cancer incidence in individuals with Down syndrome and the calcineurin pathway in the tumor vasculature is a potential target for cancer treatment.