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Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Objectives: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia.Design, Setting, Participants: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance.Main Outcome Measures: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years).Results: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted).Conclusions: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective. [ABSTRACT FROM AUTHOR]

Background Gastric cancer ( GC) is a common cause of cancer mortality. There are well-documented prognostic factors for GC but these have not been rigorously examined in an Australian context. This study examines the clinical, surgical and histopathological variables associated with survival in a GC cohort from a predominantly Caucasian-based population. Methods A multi-centre cohort of patients undergoing curative resection for GC enrolled in an ongoing tissue bank study from 1999 to 2009 was retrospectively analysed. Prospectively collected demographic, surgical and pathological variables were available for this cohort. The primary endpoints investigated were cancer-specific survival and recurrence-free survival using multivariate Cox proportional hazard modelling. Results Five-year cancer-specific survival was 45.9%, 5-year relapse-free survival was 44.7% and 30-day mortality was 2.2%. Variables showing significance on multivariate analysis for cancer-specific and relapse-free survival were AJCC stage, Lauren classification and age at surgery. Conclusion This study demonstrates that the prognostic variables for a predominantly Caucasian GC population are congruent with published prognostic features. These findings emphasize the importance of the pathological review in allocating prognosis in GC. [ABSTRACT FROM AUTHOR]

ABSTRACT We studied 17,576 members of 166 MLH 1 and 224 MSH 2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer ( CRC), endometrial cancer ( EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH 1 and MSH 2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed ( P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH 2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH 1 and MSH 2 mutation carriers are the most precise currently available. [ABSTRACT FROM AUTHOR]

Background: In the study of cancer genomics, gene expression microarrays, which measure thousands of genes in a single assay, provide abundant information for the investigation of interesting genes or biological pathways. However, in order to analyze the large number of noisy measurements in microarrays, effective and efficient bioinformatics techniques are needed to identify the associations between genes and relevant phenotypes. Moreover, systematic tests are needed to validate the statistical and biological significance of those discoveries. Results: In this paper, we develop a robust and efficient method for exploratory analysis of microarray data, which produces a number of different orderings (rankings) of both genes and samples (reflecting correlation among those genes and samples). The core algorithm is closely related to biclustering, and so we first compare its performance with several existing biclustering algorithms on two real datasets - gastric cancer and lymphoma datasets. We then show on the gastric cancer data that the sample orderings generated by our method are highly statistically significant with respect to the histological classification of samples by using the Jonckheere trend test, while the gene modules are biologically significant with respect to biological processes (from the Gene Ontology). In particular, some of the gene modules associated with biclusters are closely linked to gastric cancer tumorigenesis reported in previous literature, while others are potentially novel discoveries. Conclusion: In conclusion, we have developed an effective and efficient method, Bi-Ordering Analysis, to detect informative patterns in gene expression microarrays by ranking genes and samples. In addition, a number of evaluation metrics were applied to assess both the statistical and biological significance of the resulting bi-orderings. The methodology was validated on gastric cancer and lymphoma datasets. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor invasion and metastasis are one of the main reasons patients succumb to cancer. In this review, we summarize recent studies which provide evidence on the involvement of cells of the innate immune system and their function in invasion and metastasis. Metastasis is considered one of the hallmarks of cancer and enhanced tumor invasion and metastasis is significantly associated with cancer mortality. Metastasis occurs via a series of integrated processes involving tumor cells and the tumor microenvironment. The innate immune components of the microenvironment have been shown to engage with tumor cells and not only regulate their proliferation and survival, but also modulate the surrounding environment to enable cancer progression. In the era of immune therapies, it is critical to understand how different innate immune cell populations are involved in this process. This review summarizes recent literature describing the roles of innate immune cells during the tumor metastatic cascade. [ABSTRACT FROM AUTHOR]

Large-scale genomic studies promise to advance our understanding of the biology of human cancers and to improve their diagnosis, prognostication, and treatment. The analysis and interpretation of genomics studies have faced challenges. The retrospective and observational design of many studies has rendered them susceptible to confounding and bias. Technological variations and advances have impacted on reproducibility. Statistical hurdles in relating a large number of variables to a small number of observations have added further constraints. This review considers the promise and challenge associated with the large-scale clinically oriented genomic analysis of human cancer and attempts to emphasize potential solutions. [Copyright &y& Elsevier]