Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.

The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

The clinical significance of ERBB2 amplification/overexpression in gastric cancer remains unclear. In this study, we evaluated the ERBB2 status in 463 gastric carcinomas using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), and compared the findings with histopathological characteristics and with disease-specific survival. ERBB2 overexpression (2 þ and 3 þ ) and amplification (ratio ERBB2/CEP17X2) were found in 43 (9.3%) and 38 (8.2%) gastric carcinomas, respectively. Perfect IHC/FISH correlation was found for the 19 cases scored as 0 (all negative by FISH), and also for the 25 cases scored as 3 þ (all positive by FISH). One out of six carcinomas scored as 1 þ and 12 out of 18 carcinomas scored as 2 þ were positive by FISH. ERBB2 amplification was associated with gastric carcinomas of intestinal type (P ¼ 0.007) and with an expansive growth pattern (P ¼ 0.021). ERBB2 amplification was detected in both histological components of two mixed carcinomas, indicating a common clonal origin. A statistically significant association was found between ERBB2 amplification and worse survival in patients with expansive gastric carcinomas (P ¼ 0.011). We conclude that ERBB2 status may have clinical significance in subsets of gastric cancer patients, and that further studies are warranted to evaluate whether patients whose gastric carcinomas present ERBB2 amplification/overexpression may benefit from therapy targeting this surface receptor. Despite the trend for decreasing incidence, gastric adenocarcinoma is still the second cause of cancer death worldwide (Parkin et al, 2005). The overall 5-year survival rate of patients with resectable gastric cancer ranges from 10 to 30% (Harrison et al, 1998;Msika et al, 2000;Green et al, 2002). Apart from surgical resection, evaluation of available therapies, both neo-adjuvant and adjuvant, provides conflicting results regarding the clinical outcome. Several meta-analyses have been published in an attempt to address the discrepancies reported in the literature, but recommendation for adjuvant chemotherapy in Western centres is still not consensual (Hermans et al, 1993;Earle and Maroun, 1999;Mari et al, 2000;Gianni et al, 2001;Janunger et al, 2001Janunger et al, , 2002Hu et al, 2002). The most important prognostic factor established for gastric cancer is the TNM stage, which is determined by the depth of invasion, involvement of lymph nodes, and distant metastasis. However, clinical outcome varies among patients in the same stage (Park et al, 2006). Therefore prognostic factors other than the TNM stage, as well as new therapies, would be of great value for gastric cancer patients.The ERBB2 gene maps to 17q12 -q21 and encodes a 185-kDa transmembrane tyrosine kinase receptor (p185), which is a member of the epidermal growth factor receptor family (Xu et al, 1984;Akiyama et al, 1986;Popescu et al, 1989). In breast carcinomas, ERBB2 functions as an oncogene, as amplification of the gene induces protein overexpression in the cell membrane (Slamon et al, 1989). Besides ...

Renal cell carcinoma (RCC) represents a challenge for clinicians since the nonexistence of screening and monitoring tests contributes to the fact that one-third of patients are diagnosed with metastatic disease and 20–40% of the remaining patients will also develop metastasis. Modern medicine is now trying to establish circulating biomolecules as the gold standard of biomarkers. Among the molecules that can be released from tumor cells we can find microRNAs. The aim of this study was to evaluate the applicability of cancer-related miR-210, miR-218, miR-221 and miR-1233 as prognostic biomarkers for RCC. Patients with higher levels of miR-210, miR-221 and miR-1233 presented a higher risk of specific death by RCC and a lower cancer-specific survival. The addition of miR-210, miR-221 and miR-1233 plasma levels information improved the capacity to predict death by cancer in 8, 4% when compared to the current variables used by clinicians. We also verified that hypoxia stimulates the release of miR-210 and miR-1233 from HKC-8, RCC-FG2 and 786-O cell lines. These results support the addition of circulating microRNAs as prognostic biomarkers for RCC.