Early-onset Gastric Cancer Research Articles

Comparative investigation of early-onset gastric cancer.

Early-onset gastric cancer (EOGC) is a serious social burden. For patients with EOGC, typically considered as those aged <45 years, the underlying cause of the disease remains unclear. In addition, several misunderstandings of EOGC remain in clinical practice. Upon diagnosis, numerous patients with EOGC are already at an advanced stage (stage IV) of the disease and are unable to benefit from treatment. Moreover, several conclusions and data obtained from different EOGC studies appear to be to contradictory. The literature indicates that the incidence of EOGC is gradually rising, and that EOGC differs from traditional and familial gastric cancer in terms of clinicopathological characteristics. Patients with EOGC typically exhibit low survival rates, poor prognosis, rapid disease progression, a low degree of differentiation (signet-ring cell tumors are common) and rapid lymph node and distant metastasis, among other characteristics. The molecular genetic mechanisms of EOGC are also significantly different from those of traditional gastric cancer. An improved definition of EOCG may provide a reference for clinical diagnosis and treatment, and clear guidelines may serve as a basis for more accurate diagnosis and the development of effective treatment strategies.

Status of CHEK2 and p53 in patients with early-onset and conventional gastric cancer.

Gastric cancer (GC) is the fourth most common cause of cancer-associated death. Based on the age at diagnosis, GC is divided into early-onset GC (EOGC; ≤45 years) and conventional GC (CGC; >45 years). Mutations in the cell cycle checkpoint kinase 2 (CHEK2) and TP53 genes are associated with several types of cancer; however, their genetic defects in GC remain poorly understood. The aim of the present study was to determine the subcellular distribution of the CHEK2 protein and its redistribution following DNA damage, to improve the understanding of the DNA damage response. Genetic alterations and patterns of expression of CHEK2 and p53 proteins were investigated to identify potential biological markers and indicators of GC development. Additionally, the affected signaling pathways and their clinical importance in GC development and associated syndromes were investigated. A total of 196 GC samples (89 CGC and 107 EOGC samples) were used in the present study. DNA from 53 samples (18 CGC and 35 EOGC samples) was sequenced using targeted next-generation sequencing technology to identify and compare common and rare mutations associated with GC. Subsequently, the cytoplasmic and nuclear expression levels of CHEK2, phosphorylated (p)-CHEK2 at threonine 68 and p53 in GC tissues were determined via immunohistochemistry. Sequencing resulted in the identification of 63 single nucleotide polymorphisms (SNPs) in the CHEK2 gene amongst 5 different variants, and the intron variant c.319+379A>G was the most common SNP. In the TP53 gene, 57 different alterations were detected amongst 9 variant types, and the missense variant c.215C>G was the most common. Nuclear CHEK2 expression was high in both the EOGC and CGC subtypes. However, the prevalence of cytoplasmic CHEK2 expression (P<0.001) and nuclear p-CHEK2 expression (P=0.011) was significantly higher in CGC compared with in EOGC tissues. There was a statistically significant difference between high and low cytoplasmic CHEK2 expression in patients with p53-positive EOGC compared with in patients with p53-positive CGC (P=0.002). The present study was designed to determine the association between CHEK2 and p53 expression patterns in patients with EOGC and CGC, as well as genetic alterations in the CHEK2 and TP53 genes.

Incidence of early-onset gastric and esophagus cancers has changed over time with disproportionate impact on Black and Hispanic patients.

171 Background: The increased incidence of gastro-esophageal junction adenocarcinoma has been well-described, but how the proportion of early versus older onset cancer has changed over time remains incompletely understood. This study characterized the socioeconomic and pathologic characteristics of early-onset gastro-esophageal malignancies. Methods: All patients with gastric cancer (GC) and esophageal cancer (EC) from 2004-2015 in the National Cancer Database were included and categorized by age under or over 60 years. Differences in demographics, disease stage, treatment characteristics and socioeconomic factors between young and older patients were assessed by Chi-square test. The effect of age, race, insurance status, community median income and community educational attainment on overall survival (OS) were assessed using uni- and multivariable Cox models with Bonferonni correction when indicated. Results: The study population comprised 158,599 patients with GC and 139,210 patients with EC. For GC, 43,146 patients (27.2%) were under age 60. The proportion of patients diagnosed under 60 increased over time: 26.7% in 2004-2006, 26.9% in 2007-2009, 27.6% in 2010-2012 and 27.5% in 2013-2015. Compared to older patients, young patients were more likely to be Black (16.7% vs. 13.2%), Asian (7.6% vs. 6.1%) or Hispanic (15.5% vs. 7.7%), diagnosed with stage 4 disease (43.5% vs. 31.3%) and to have poorly differentiated grade (61% vs. 51.7%), p value &lt; 0.0001 for all. For EC, 38,801 patients (27.8%) were under age 60. The proportion of patients diagnosed under 60, decreased over time: 29.6% in 2004-2006, 28.3% in 2007-2009, 27.6% in 2010-2012 and 26.2 % in 2013-2015. Compared to older patients, young patients were more likely to be Black (12.6% vs. 8.2%) or Hispanic (4.2% vs. 3.1%), diagnosed with stage 4 disease (34.3% vs. 26.1%), p value &lt; 0.0001 for all. There was no difference in histologic grade between younger and older patients (41.1% vs. 40.3%, p = 0.85). Age &lt; 60 years was associated with improved OS in both GC and EC. After adjusting for other demographic, socioeconomic, disease stage and treatment-related factors, Black patients had the worst median OS compared to other races in both malignancies as shown in the Table. Conclusions: Early-onset GC has increased over time while early-onset EC has decreased. Patients with early-onset gastric and esophageal cancer are more likely to be Black or Hispanic and to present with stage 4 cancer. Younger patients with GC are also more likely to have poorly differentiated histology. Most concerning, Black patients have the worst OS compared to other races for both GC and EC. [Table: see text]

Clinical and molecular characteristics of early-onset versus average-onset esophagogastric cancer.

250 Background: While the rate of esophagogastric (EG) cancer is declining, early onset (EO) gastric cancer prior to age 50 is rising. It is unknown whether EO-EG cancer represents a distinct entity. This study investigates the clinical and molecular characteristics of EO compared with average onset (AO)-EG cancers. Methods: We reviewed clinical and molecular features of gastric (G), esophageal (E) and gastroesophageal junction (GEJ) cancer in patients treated at MSKCC between 2005 and 2018. We defined early onset as age &lt; 49, based on the age cutoff for urgent endoscopy referral. Clinical symptoms at diagnosis, primary tumor location, histology, HER2 and MSI status and molecular alterations were compared using Fisher’s exact test. Benjamini-Hochberg method was used to decrease the false discovery rate. Results: We analyzed 738 pts with EG cancer (age &lt; 49 n=151; age &gt;50 n=587). Race and sex were different with more Asian (19% vs. 9%), fewer Caucasian (62% vs. 81%) ( P&lt;0.001) and more female patients (40% vs. 29%, P=0.014) in the EO group. Time from symptom onset to diagnosis was longer in the EO group (median (IQR) 144 d (66-276) vs. 75 d (34-136), P=0.009), though stage did not differ ( P=0.49). Patients with EO-EG cancer had less weight loss ( P&lt;0.001), but no other distinct presenting symptoms. Primary disease site was different with more gastric in the EO group (66% vs. 55%, P=0.04). Signet-ring histology was more common in the EO group (11% vs. 3%; P=0.0009). ERBB2 amp and MSI-H were similar, with a trend toward more MSI-H in the AO group (ERBB2 amp P=0.88, Q=0.830; MSI-H P=0.0157, Q=0.056). The most frequent somatic alterations were similar in EO vs. AO pts, including TP53 (68% vs. 70%, P=0.370, Q=0.825), CDH1 (15% vs. 11%, P=0.139, Q=0.825), RHOA (6% vs. 5%, P=0.395, Q=0.825). There was a trend toward more ARID1A (19% vs. 7%, P&lt;0.01, Q=0.250) and FBWX7 (5% vs. 2%, P=139, Q=0.825) mutations in the AO group. Conclusions: Presenting symptoms, stage, histology, HER2 and MSI status are similar in patients with EO vs. AO-EG cancer. There is a trend in EO toward longer time to diagnosis, gastric primary site of disease, signet-ring histology and fewer ARID1A and FBWX7 mutations. Expanded clinical and molecular data will be presented. [Table: see text]

High-Throughput Sequencing of Gastric Cancer Patients: Unravelling Genetic Predispositions Towards an Early-Onset Subtype.

Background: Gastric cancer is the fourth most common cause of cancer-related death. Currently, it is broadly accepted that the molecular complexity and heterogeneity of gastric cancer, both inter- and intra-tumor, display important barriers for finding specific biomarkers for the early detection and diagnosis of this malignancy. Early-onset gastric cancer is not as prevalent as conventional gastric carcinoma, but it is a preferable model for studying the genetic background, as young patients are less exposed to environmental factors, which influence cancer development. Aim: The main objective of this study was to reveal age-dependent genotypic characteristics of gastric cancer subtypes, as well as conduct mutation profiling for the most frequent alterations in gastric cancer development, using targeted next-generation sequencing technology. Patients and methods: The study group included 53 patients, consisting of 18 patients with conventional gastric cancer and 35 with an early-onset subtype. The DNA of all index cases was used for next-generation sequencing, employing a panel of 94 genes and 284 single nucleotide polymorphisms (SNPs) (TruSight Cancer Panel, Illumina), which is characteristic for common and rare types of cancer. Results: From among the 53 samples processed for sequencing, we were able to identify seven candidate genes (STK11, RET, FANCM, SLX4, WRN, MEN1, and KIT) and nine variants among them: one splice_acceptor, four synonymous, and four missense variants. These were selected for the age-dependent differentiation of gastric cancer subtypes. We found four variants with C-Score ≥ 10, as 10% of the most deleterious substitutions: rs1800862 (RET), rs10138997 (FANCM), rs2230009 (WRN), and rs2959656 (MEN1). We identified 36 different variants, among 24 different genes, which were the most frequent genetic alterations among study subjects. We found 16 different variants among the genes that were present in 100% of the total cohort: SDHB (rs2746462), ALK (rs1670283), XPC (rs2958057), RECQL4 (rs4925828; rs11342077, rs398010167; rs2721190), DDB2 (rs326212), MEN1 (rs540012), AIP (rs4930199), ATM (rs659243), HNF1A (rs1169305), BRCA2 (rs206075; rs169547), ERCC5 (rs9514066; rs9514067), and FANCI (rs7183618). Conclusions: The technology of next-generation sequencing is a useful tool for studying the development and progression of gastric carcinoma in a high-throughput way. Our study revealed that early-onset gastric cancer has a different mutation frequency profile in certain genes compared to conventional subtype.

A validated survival nomogram for early-onset diffuse gastric cancer.

This study aimed to establish and independently validate a prognostic nomogram for individual risk prediction in patients with early-onset diffuse gastric cancer (EODGC). Data for 794 patients with EODGC from the SEER database were randomly assigned to training (N=558) and internal validation (N=236) sets, and data for 82 patients from the Renmin Hospital of Wuhan University (RMHWHU) were used as an independent validation cohort. Our LASSO regression analyses of the training set yielded five clinicopathological features (race, AJCC stage, surgery for primary site, chemotherapy and tumor size), which were used to create a survival nomogram. Our survival nomogram achieved better predictive performance than the AJCC staging system, the current standard. Additionally, the calibration curves of the prognostic nomogram revealed good agreement between the predicted survival probabilities and the ground truth values. Indeed, our nomogram, which estimates individualized survival probabilities for patients with EODGC, shows good predictive accuracy and calibration ability for both the SEER and RMHWHU cohorts. These results suggest that a survival nomogram may be better at predicting OS for EODGC patients than the AJCC staging system.

Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies.

Gastric cancer (GC) is one of the most common malignancies worldwide and it is the fourth leading cause of cancer-related death. GC is a multifactorial disease, where both environmental and genetic factors can have an impact on its occurrence and development. The incidence rate of GC rises progressively with age; the median age at diagnosis is 70 years. However, approximately 10% of gastric carcinomas are detected at the age of 45 or younger. Early-onset gastric cancer is a good model to study genetic alterations related to the carcinogenesis process, as young patients are less exposed to environmental carcinogens. Carcinogenesis is a multistage disease process specified by the progressive development of mutations and epigenetic alterations in the expression of various genes, which are responsible for the occurrence of the disease.

Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer

PurposeCTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied. MethodsDe-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers. ResultsFifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. ConclusionCTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.

Aggressive case of early onset gastric cancer; identifying the knowledge gap

A woman aged 30 years was referred for endoscopy for iron deficiency anaemia. Colonoscopy was normal. Upper endoscopy demonstrated multiple small, carpet-like, sessile polyps in the gastric fundus and a...

Frequency and Clinical Characteristics of Unselected Korean Gastric Cancer Patients with a Germline CDH1 V832M Mutation

Background: Germline mutations in CDH1 are associated with hereditary and early onset- diffuse gastric cancer. However, the frequency of CDH1 germline mutation in unselected gastric cancer cases is not well established.Aim: The aim of this study was to investigate the frequency and clinical characteristics of germline CDH1 V832M mutation carriers in unselected Korean gastric cancer cases.Methods: Direct sequencing was performed to determine the presence of CDH1 V832M in 305 unselected Korean gastric cancer patients. Lauren's histologic type, family history of gastric cancer, and age of cancer diagnosis were compared between V832M carriers and non-carriers.Results: In the study population, seven gastric cancer patients (7/305, 2.29%) were found to have the CDH1 V832M mutation. The CDH1 V832M mutation carrier state was not significantly associated with phenotypes including Lauren's histologic type, family history of gastric cancer, age of cancer diagnosis, and other cancer history in a patient.Conclusion: This study demonstrates that the germline CDH1 V832M mutation is common in sporadic, late onset, and intestinal type gastric cancer as well as familial, early onset, and diffuse type gastric cancer. Our finding suggests that guidelines for managing CDH1 mutation carriers should be refined through additional data on penetration according to CDH1 mutation type in sporadic cases.

Development and validation of prognostic nomogram for young patients with gastric cancer

This study was to establish nomogram models for prognostic evaluation of early-onset gastric cancer (EOGC) in both overall survival (OS) and cancer-specific survival (CSS). EOGC patients from 2004 to 2015 were retrieved from the surveillance, epidemiology and end results (SEER) and further randomly assigned to training and validation sets. Univariate and multivariate cox analysis was used to screen out significant variables for construction of nomogram. Nomogram models were assessed by concordance index (C-index), calibration plot, receiver operating characteristics (ROCs) curve and decision curve analysis (DCA). A total of 549 EOGC were selected in this process. OS nomogram was constructed based on tumor size and tumor site. CSS nomogram was constructed based on tumor size, SEER stage and tumor site. In training set, C-index for the OS nomogram was 0.688 [95% confidence intervals (95% CI): 0.629-0.747], CSS nomogram 0.785 (95% CI: 0.735-0.835). In the external validation, the C-index for the OS nomogram was 0.633 (95% CI: 0.579-0.687), while for the CSS nomogram 0.733 (95% CI: 0.686-0.780). High quality of calibration plots both in OS and OS nomogram models was noticed. Nomograms displayed a comparable result to tumor-node-metastasis (TNM) stage and SEER stage for EOGC based on DCA. The nomogram models provided an insightful and applicable tool to evaluate the prognosis of EOGC both in OS and CSS.

808P - Investigation on gastric cancer susceptibility genes in Chinese early-onset diffuse gastric cancer

BackgroundHereditary diffuse gastric cancer (HDGC) is closely related to germline mutation of CDH1. In addition, potential pathogenic germline variants in other candidate genes were detected in FGC and HDGC families. However, comprehensive genetic profile of HDGC predisposing gene variants in Chinese Familial gastric cancer (FGC) and HDGC patients are yet to be elucidated. MethodsWe collected peripheral blood from 28 early-onset DGC patients and from a first degree relative DGC patient who was diagnosed at age of 50. All 29 patients fulfilled IGCLC 2015 criteria for HDGC clinical diagnosis and genetic testing. Genomic DNA was extracted from peripheral blood followed by Whole Exome Sequencing (WES) with average sequencing depth of at least 100X. Gastricancer predisposing SNV and Indel candidates were filtered based on population allele frequencies in public nucleotide polymorphism databases and corresponding functional impact was predicted by in silico tools. ResultsAmong previously reported gastric cancer susceptibility genes, CDH1, BRCA2, MAP3K6 expressed the most predisposing SNV and Indel candidates. In addition, a novel splice-site variant, c.2165-1G>A, in CDH1 was detected in a Chinese early-onset HDGC patient who developed ovarian metastasis. Moreover, BCR gene exhibited as the most prevalent gastric cancer predisposing gene with filtered variants primarily enriched in RhoGAP domain. Pathway enrichment analysis showed that the top three predisposing variant candidates were enriched in the following signalling pathway: ECM-receptor interaction (P-Value: 0.001), focal adhesion (P-Value: 0.02) and protein digestion and absorption (P-Value: 0.002). ConclusionsThis study suggested that CDH1, BRCA2, MAP3K6 may act as potential gastric cancer susceptibility genes in Chinese early-onset HDGC patients. Further study may be required to investigate the functional role of BCR abnormality, especially in its RhoGAP domain, in the tumorigenesis of gastric cancer. Moreover, to further investigate molecular mechanisms of early-onset gastric cancer, one may consider genes involved in three signalling pathways: ECM-receptor interaction, focal adhesion and protein digestion and absorption. Legal entity responsible for the studyPeking University Cancer Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features

BackgroundOverall the incidence of gastric cancer is declining in the United States; however, the incidence of early-onset gastric cancer is increasing. We sought to elucidate clinical and genomic characteristics and risk factors for early-onset gastric cancer compared with late-onset gastric cancer. MethodsWe utilized the Surveillance, Epidemiology, and End Results database (1973–2015), the Behavioral Risk Factor Surveillance Survey, and The Cancer Genome Atlas to characterize early-onset gastric cancer. ResultsThe incidence of early-onset gastric cancer increased during the study period and now comprises >30% of all gastric cancer in the United States. Early-onset gastric cancer was associated with higher grade (55.2 vs 46.9%), signet-ring cells (19.0 vs 10.4%), diffuse histology (25.7 vs 15.0%), and metastatic disease (49.5 vs 40.9%, all P < .01) compared with late-onset gastric cancer. Early-onset gastric cancer was more likely to be Epstein-Barr virus (7.7 vs 5.1%) or genomically stable (22.5 vs 8.1%) subtype, whereas late-onset gastric cancer was more likely to be microsatellite instability subtype (18.6 vs 5.6%; all P < .01). Risk factors for gastric cancer were less correlated with early-onset gastric cancer compared with late-onset gastric cancer. ConclusionThe incidence of early-onset gastric cancer has been steadily increasing in the United States, comprising >30% of new gastric cancer cases today. Early-onset gastric cancer is genetically and clinically distinct from traditional gastric cancer. Additional investigations are warranted to better understand this alarming phenomenon.

Hereditary diffuse gastric cancer: cancer risk and the personal cost of preventive surgery

Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer (DGC) and female carriers have an additional risk of lobular breast cancer. The reported literature GC risk of 70% has led to the recommendation for germline mutation carriers to undergo prophylactic total gastrectomy (PTG). The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD = 25.6), which is better than reference values from the general populations in USA and Canada Role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for QOL (p < 0.05). Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance QOL. The function/symptom scores were associated with worse overall health and global health status and thus may mark a real need for more attentive post-surgical care.

Genetics of gastric cancer: what do we know about the genetic risks?

An appreciable number of patients with gastric cancer have an underlying hereditary cancer susceptibility syndrome as the cause of their gastric cancer, particularly those with early onset gastric cancer or a family history of gastric or other cancers. Pathogenic germline variants in specific genes account for the known gastric cancer predisposition syndromes. Germline genetic testing can identify individuals and their family members who carry inherited pathogenic gene variants, and thus have increased risk of developing gastric or other cancers. Ideally, germline pathogenic variants can be identified in family members before the onset of disease, when early detection or prevention strategies can be implemented most effectively to decrease gastric cancer- related morbidity and mortality. This article reviews some of the currently known gastric cancer predisposition syndromes and their associated cancer risks. We also discuss current research and advances in the field of genetic gastric cancer susceptibility.

Expression of DNA Damage Response Markers in Early-Onset or Familial Gastric Cancers

Background:Early-onset or familial gastric cancer (GC) is known to have clinicopathologic profiles different from those of sporadic GC. We aimed to compare DNA damage response marker expression between early-onset or familial GC and sporadic GC.Methods:GC samples were obtained from patients who underwent gastrectomy for GC at Seoul National University Hospital. Immunohistochemical analyses of various DNA damage response markers, including BRCA1, BRCA2, MRE11, RAD51C, and γH2AX, were performed using 54 early-onset GC, 59 familial GC, and 337 sporadic GC tissue microarray samples. Correlations between marker expression and clinicopathologic features were evaluated by univariate and multivariate analyses, and overall survival was analyzed.Results:The rate of γH2AX positivity was significantly higher (p < 0.001) in early-onset or familial GC than in sporadic GC. In contrast, the rates of MRE11 negativity and RAD51C negativity were significantly higher in sporadic GC than in early-onset or familial GC. BRCA1 negativity was associated with decreased overall survival in sporadic GC (p = 0.002), and MRE11 negativity was associated with decreased overall survival in sporadic GC (p = 0.012).Conclusion:Our results show significant differences in DNA damage response marker expression between early-onset or familial GC and sporadic GC.

Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil

IntroductionThe contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, ≤ 55 years old) patients.MethodologyFrom 2013 to 2015, a total of 88 unrelated and consecutive patients diagnosed with EOGC were enrolled. All CDH1 exons and intronic boundaries were sequenced, and large genomic rearrangements were screened by MLPA. CDH1 transcription analysis was performed for variants that could potentially induce an effect on splicing. The diet and lifestyle habits of EOGC patients were compared to Brazilian population diet and lifestyle, obtained from governmental databases.ResultsOf 88 patients, the mean age at EOGC diagnosis was 39 years and 55% fulfilled the criteria for hereditary diffuse gastric cancer. The majority of the tumors were diffuse (74%) and poorly differentiated (80%). In total, 4 novel missense variants of uncertain significance (VUS) were identified: c.313T>A, c.387G>T, c.1676G>A, and c.1806C>A. The MLPA results revealed no rearrangements and CDH1 transcription analysis for variants of interest were inconclusive. EOGC patients had a higher red (OR:2.6, 95%CI:1.4–4.9) and processed (OR:3.1, 95%CI:1.6–6.0) meat intake and higher fruit consumption (OR:0.4, 95%IC:0.3–0.7) compared to eating habits of the Brazilian population.ConclusionsNo unequivocal pathogenic germline CDH1 variants were identified in Brazilian EOGC patients. Dietary habits may be associated with the EOGC development.

Proteogenomic Characterization of Human Early-Onset Gastric Cancer

We report proteogenomic analysis of diffuse gastric cancers (GCs) in young populations. Phosphoproteome data elucidated signaling pathways associated with somatic mutations based on mutation-phosphorylation correlations. Moreover, correlations between mRNA and protein abundances provided potential oncogenes and tumor suppressors associated with patient survival. Furthermore, integrated clustering of mRNA, protein, phosphorylation, and N-glycosylation data identified four subtypes of diffuse GCs. Distinguishing these subtypes was possible by proteomic data. Four subtypes were associated with proliferation, immune response, metabolism, and invasion, respectively; and associations of the subtypes with immune- and invasion-related pathways were identified mainly by phosphorylation and N-glycosylation data. Therefore, our proteogenomic analysis provides additional information beyond genomic analyses, which can improve understanding of cancer biology and patient stratification in diffuse GCs.

Exploring the differences between early-onset gastric cancer and traditional-onset gastric cancer.

The current study sought to explore the potential clinical, epidemiological and genetic differences between early-onset gastric cancer (E-gastric cancer: defined as 20-39 years) and traditional-onset gastric cancer (T-gastric cancer: defined as ≥40 years). Datasets from the following sources were searched: Surveillance, Epidemiology and End Results database [2000-2014], Behavioral Risk Factor Surveillance Survey and the cancer genome atlas (TCGA). Clinicopathological characteristics, trends, and genetic findings were compared between E-gastric cancer and T-gastric cancer. Moreover, correlations with relevant risk factors were sought after. A total of 95,323 gastric cancer patients were identified in the period from 2000 to 2014. While T-gastric cancer was decreasing during the study period (-1.4; P<0.05), E-gastric cancer was stable during the study period. E-gastric cancer is less prevalent in males (51.1% vs. 61.0%; P<0.0001), and white patients (68.9% vs. 71.4%; P<0.0001). E-gastric cancer patients usually present with poorly differentiated histology (55.3% vs. 48.0%; P<0.0001) as well as more aggressive histological subtypes (e.g., diffuse histology or linitis plastica). No difference can be detected with regards to risk factor correlations between E-gastric cancer and T-gastric cancer. Only four patients with E-gastric cancer were available in the provisional TCGA dataset at the time of the study. E-gastric cancer is a potentially distinct disease entity with specific clinicopathological and trend patterns compared to conventional T-gastric cancer. Further studies are needed to explore the potential etiologic basis as well as to investigate the clinical consequences of this distinction. The impact of this distinction on minority populations requires further assessment as well.

Helicobacter pylori associated factors in the development of gastric cancer with special reference to the early-onset subtype.

Nowadays, gastric cancer is one of the most common neoplasms and the fourth cause of cancer-related death on the world. Regarding the age at the diagnosis it is divided into early-onset gastric carcinoma (45 years or younger) and conventional gastric cancer (older than 45). Gastric carcinomas are rarely observed in young population and rely mostly on genetic factors, therefore provide the unique model to study genetic and environmental alternations. The latest research on early-onset gastric cancer are trying to explain molecular and genetic basis, because young patients are less exposed to environmental factors predisposing to cancer. In the general population, Helicobacter pylori, has been particularly associated with intestinal subtype of gastric cancers. The significant association of Helicobacter pylori infection in young patients with gastric cancers suggests that the bacterium has an etiologic role in both diffuse and intestinal subtypes of early-onset gastric cancers. In this paper we would like to ascertain the possible role of Helicobacter pylori infection in the development of gastric carcinoma in young patients. The review summarizes recent literature on early-onset gastric cancers with special reference to Helicobacter pylori infection.