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Abstract: Aim: Mitogen-activated protein kinase (MAPK) cascade and phosphatidylinositol 3-kinase (PI3K) survival pathways are frequently activated in the progression of gastrointestinal malignancies. In this study, we aimed to determine the frequency of gene mutations in members of these pathways – Epithelial Growth Factor Receptor (EGFR), KRAS, BRAF, PIK3CA and MLK3 in a series of 63 gastric carcinomas with high levels of microsatellite instability (MSI). Methods: Gene mutation analysis was performed by PCR amplification followed by direct sequencing. In selected tumour cases, EGFR expression was evaluated by immunohistochemistry. Association studies between molecular data and clinicopathologic characteristics were performed. Results: Mutations in EGFR (3′-untranslated region [UTR] polyA repeat), KRAS, PIK3CA and MLK3 genes occurred in 30 (47.6%), 11 (17.5%), 9 (14.3%) and 2 (3.2%) of the MSI gastric cancer (GC) cases, respectively. No BRAF or EGFR hotspot mutations were identified. Overall, mutations in at least one of these genes were found in 55.6% (35/63) of gastric carcinomas. From those mutant cases 40.0% (14/35) of them had concomitant gene mutations, always involving EGFR polyA deletions. Interestingly, we observed significant associations between oncogenic mutations and female gender (p =0.046) old age of diagnosis (p =0.001) and intestinal subtype (p =0.043). Conclusion: Our results show that MSI gastric carcinoma frequently shows activation of EGFR-MAPK and PI3K pathways. Within all alterations found, deletions of the A13 repeats of EGFR were common, suggesting this molecular event as an important biomarker for stratification of GC patients for treatment with EGFR inhibitors. [Copyright &y& Elsevier]

Purpose: X-ray repair cross complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the bas-excision repair pathway. Several single-nucleotide polymorphisms in the XRCC1 gene are identified and related with increased cancer risk development. In particular, the -77T>C polymorphism located on the promoter region relates with lung cancer risk development. The aim of this study is to analyze the -77T>C allelic frequencies in a population composed of 456 primary gastric cancer patients (GC) and 507 blood donor controls.Methods: GC patients were observed at the University of Siena, Italy; clinicopathological data and family history were available for the cancer group. The control group is composed of blood donors. Constitutional genomic DNA was PCR amplified, and XRCC1 -77T>C was detected using restriction enzyme BsrB I and analyzed in a 3% agarose gel.Results: The -77C>C homozygous genotype was significantly associated with increased risk of gastric cardia carcinoma (p = 0.023) with an odds ratio of 1.65 (95% confidence interval 1.14 to 2.4). In the family history stratification, we report a significant association (p = 0.043) between the -77T>C polymorphism and GC cases with familial lung cancer aggregation.Conclusions: Our results suggest that the XRCC1 -77T>C polymorphism is a relevant host susceptibility factor for gastric cardia cancer development and specific subsets of familial clustering of GC. [ABSTRACT FROM AUTHOR]

Simple Summary: E-cadherin (CDH1 gene) germline mutations are associated with the development of the autosomal cancer syndrome known as hereditary diffuse gastric cancer. About 30% of families fulfilling the clinical criteria established by the International Gastric Cancer Linkage Consortium have constitutional alterations of the CDH1 gene. Different patterns of CDH1 germline mutations have described as truncating, deletion, insertion, splice site, non sense, silence, and at last, missense alterations. The frequency of the different E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has reported extremely variable. In this study we aimed to assess the worldwide frequency of CDH1 germline mutations in gastric cancers coming from different geographical areas, using a systematic approach. Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease. [ABSTRACT FROM AUTHOR]

E-cadherin (CDH1 gene) germline mutations are associated with the development of diffuse gastric cancer in the context of the so-called hereditary diffuse gastric syndrome, and with an inherited predisposition of lobular breast carcinoma. In 2019, the international gastric cancer linkage consortium revised the clinical criteria and established guidelines for the genetic screening of CDH1 germline syndromes. Nevertheless, the introduction of multigene panel testing in clinical practice has led to an increased identification of E-cadherin mutations in individuals without a positive family history of gastric or breast cancers. This observation motivated us to review and present a novel multidisciplinary clinical approach (nutritional, surgical, and image screening) for single subjects who present germline CDH1 mutations but do not fulfil the classic clinical criteria, namely those identified as—(1) incidental finding and (2) individuals with lobular breast cancer without family history of gastric cancer (GC). [ABSTRACT FROM AUTHOR]