Somatic Alteration Characteristics of Early-Onset Gastric Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhou Q
PROVIDER: S-EPMC9054482 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Somatic Alteration Characteristics of Early-Onset Gastric Cancer.
Zhou Qiyang Q Tao Feng F Qiu Liqing L Chen Hanlin H Bao Hua H Wu Xue X Shao Yang Y Chi Liangjie L Song Hu H
Journal of oncology 20220422
Gastric cancer is one of the most common and deadly cancer types worldwide, which brings millions of dollars of economic loss each year. Patients diagnosed with early-onset gastric cancer were reported to have a worse prognosis compared to other gastric cancer patients, while the mechanisms behind such phenomenon are unknown. To identify age-dependent somatic alternations in gastric cancer, next-generation sequencing targeting 425 genes was performed on 1688 gastric tumor tissues and correspondi ...[more]
Similar Datasets
Project description:Previous studies reported substantial differences between proximal and distal gastric cancer, however, most of the cases included in these studies were advanced gastric cancers (AGCs). The aim of this study was to investigate the unique characteristics of proximal early gastric cancer (EGC) by comparing with distal EGC. From March 2007 to March 2016, proximal and distal EGC patients who underwent endoscopic or surgical resection at our institution were matched 1:3 according to age and sex. We retrospectively analyzed the clinical and histopathological information. A total of 368 patients were enrolled including 92 (25%) in the proximal and 276 (75%) in the distal group. The proportion of patients who underwent surgery (56.5 vs. 20.3%, p<0.001), undifferentiated type (38.0 vs. 19.6%, p<0.001), tumor size (29.5 ±19.4 vs. 20.3 ±16.8 mm, p<0.001) and submucosal (SM) invasion (60.9 vs. 25.7%, p<0.001) were significantly higher in the proximal group than in the distal group. In multivariate analysis, the proximal location of EGC was a significant risk factor for SM invasion in the total population (odds ratio [OR], 3.541; 95% confidence interval [CI], 2.053-6.110; p<0.001), and in subgroup with EGC < 30mm (n = 279) (OR, 5.940; 95% CI, 2.974-11.862; p<0.001). In conclusion, careful therapeutic decision of proximal EGC is essential due to the different histopathological characteristics such as large tumor size and higher potential for SM invasion.
| S-EPMC6764682 | biostudies-literature
Project description:Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (HER2 negative) breast cancer. Thirteen of 79 unselected very young patients were BRCA1/2 germline mutation carriers. Of the non-BRCA tumors, eight with luminal subtype (HER2 negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were PIK3CA, GATA3, TP53 and MAP2K4. Potential cancer drivers affected in the present non-BRCA tumors include GRHL2, PIK3AP1, CACNA1E, SEMA6D, SMURF2, RSBN1 and MTHFD2. Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1, MUTYH, PALB2, POLD1, POLE, RAD9A, RAD51 and TP53, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.
| S-EPMC5976478 | biostudies-literature
Project description:Although gastric cancer (GC) is most common in the elderly population, the rate of early-onset gastric cancer (EOGC) is increasing each year. In this study, the clinicopathological information of 9,406 patients who underwent GC resection in our institution from 2000 to 2019 was collected. We compared the clinicopathological characteristics between the EOGC group, in which patients were younger than 40, and the control group, summarizing the evolutionary trends of the EOGC group's characteristics. Then, we focused on the characteristics of EOGC in different sex groups and the evolutionary trends of female EOGC patients' clinicopathological characteristics. The results showed that a greater proportion of the EOGC group was female (47.32% vs. 23.53%), had poorly differentiated adenocarcinoma (84.78% vs. 64.11%), gastric antrum cancer (59.38% vs. 50.72%) and signet ring cell carcinoma (21.13% vs. 8.51%). Over the past 20 years, the proportion of EOGC patients with T4 stage (10.71% to 41.74%), N3 stage (0 to 30.73%) and poorly differentiated adenocarcinoma (70.37% to 92.23%) has increased. In the female EOGC group, there were more patients with stage III-IV disease (57.23% vs. 43.22%), T4 stage (35.85% vs. 22.60%), and poorly differentiated adenocarcinoma (91.88% vs. 78.68%). Additionally, the proportions of T4 stage (16.13% to 50.50%), N3 stage (0% to 31.68%), and poorly differentiated adenocarcinoma (69.23% to 98.97%) gradually increased. In conclusion, our study not only identified unique clinicopathological characteristics of EOGC but also revealed the evolutionary trends of these indicators, which may provide some theoretical basis for the prevention and diagnosis of EOGC.
| S-EPMC9251691 | biostudies-literature
Project description:Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.
| S-EPMC8269053 | biostudies-literature
Project description:BackgroundThe rising incidence of early onset colorectal cancer (EOCRC) might reflect a novel tumour entity.AimsTo evaluate clinicopathological characteristics of sporadic EOCRC (in patients < 50 years old) and investigate changes over time METHODS: All patients with sporadic EOCRC between 1989 and 2016 were included and divided by age: 20-29 years (group I), 30-39 years (group II) and 40-49 years (group III).ResultsWe included 6400 patients. The presence of signet-ring cells and more poorly differentiated tumours were more common in the younger age groups: 5.4% and 3.7% for signet-ring cells in group I and II vs 1.4% in group III (P < 0.01), and 28.5% and 20.3% for poorly differentiated in group I and II vs 16.6% in group III, (P < 0.01 group I; P = 0.07 group II). Positive lymph nodes were more frequently observed in the younger age groups: 16.2% in group I vs 9.3% in group II (P = 0.01) and 7.9% (P < 0.01) in group III. Over time, a greater proportion of CRCs were diagnosed in women in group I (34.5% < 2004 vs 54.9%>2005, P = 0.09), and a higher percentage of rectal cancer was found in age group III (34.3% < 2004 vs 40.7% > 2005, P < 0.01). Mean overall survival was 6.3 years and improved over time.ConclusionsEOCRC is not only characterised by age of onset but also by the more frequent presence of signet-ring cells, more poorly differentiated tumours, and higher risk of lymph node metastases. In the most recent years, a higher proportion of rectal cancer was found from the age of 30 years, and a higher proportion of CRCs were diagnosed in females below the age of 30 years.
| S-EPMC9292775 | biostudies-literature
Project description:Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. Genetic factors are implicated, including DNA mismatch repair (MMR) deficiency manifested as tumor microsatellite instability (MSI). However, a standardized panel of markers and a definition of low-versus-high level MSI in GC are lacking. We examined a population-based cohort of early onset (<or=50 yrs) gastric cancer. We identified 211 cases of early onset gastric cancer in Central-East Ontario from 1989 to 1993, with archival material available for 139 cases. Testing included a six-mononucleotide marker panel and a three-MMR immunohistochemical panel. Overall, 30% (41 of 139) of GC were MSI+, with allelic shifts at one to eight markers. An unexpected discordance between the BAT-25, BAT-26, and BAT-40 markers was observed in the MSI+ cases. Six cases showing multiple loci instability (>or=3 markers MSI+/MSI-high) demonstrated MMR protein deficiency. Three novel hMLH1 mutations (two germline frameshift and one somatic nonsense) were also found. The only significant clinicopathological associations were increased tumor size in MSI+ cases (P=0.04) and Lauren histotype (P=0.006) and tumor grade (P=0.007) in MSI-high cases. Tumor size, location, depth, nodal status, and Ming subtype were significant prognostic variables. Therefore, we propose a new definition of high-level MSI based on unifying characteristics of instability of more than or equal to three of six mononucleotide markers and loss of MMR protein expression.
| S-EPMC1888489 | biostudies-literature
Project description:We report proteogenomic analysis of diffuse gastric cancers (GCs) in young population. 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.
2018-12-06 | GSE122401 | GEO
Project description:Background & aimsEarly-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients.MethodsWe conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays.ResultsWe identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells.ConclusionsIn an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.
| S-EPMC6863080 | biostudies-literature
Project description:The AT-rich Interactive Domain 1A (ARID1A) is one of the most frequently mutated genes in gastric cancer. Here, we found that genetic variants in noncoding regions of ARID1A associated with altered protein levels by target sequencing. Notably, tumors with ARID1A variants in the 3'untranslated region (3'UTR) exhibited remarkably increased heterogeneity of ARID1A protein. In general, genetic variants and protein deficiency of ARID1A in tumors were associated with a better survival. Strikingly, altered patterns and heterogeneity of ARID1A protein expression were observed in peritumor tissues and carried significant implications in defining tumor immune contexture by multiplex immunohistochemistry. By analyzing the spatial distribution of TILs, we showed that reduced ARID1A protein levels in both tumor and peritumor tissues were significantly correlated with increased density and proximity of TILs to tumor cells. In contrast, high heterogeneity of ARID1A expression was associated with increased TIL density, but reduced proximity of TILs to tumor cells. Collectively, our study characterized ARID1A genetic alterations and its protein expression patterns in EOGC, demonstrating new strategies for clinically assessing its molecular impact on tumor onset and progression, tumor immune response, and patient survival.
| S-EPMC7716160 | biostudies-literature
Project description:BackgroundGastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear.AimsTo examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC <50 years old).Methods211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry.Results1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer.ConclusionThis is the first population-based study, in a low-incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2-3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.
| S-EPMC2563190 | biostudies-literature