Familial Intestinal Gastric Cancer Research Articles

Abstract C158: Contribution of multi-organ cancer predisposition genes for gastric cancer risk of different histological subtypes

Abstract Approximately 10% of gastric cancer (GC) cases exhibit familial clustering, yet only 1-3% can be explained by known hereditary syndromes, being Hereditary Diffuse Gastric Cancer (HDGC) the most well-established disease predisposing for diffuse gastric cancer. Familial intestinal gastric cancer (FIGC) has been defined clinically, but it remains mostly genetically unexplained. Likewise, the heritability of mixed GC remains to be uncovered. We aimed to estimate the frequency of known cancer predisposition gene variants in GC cases with family history of cancer and/or early onset. We evaluated the contribution of pathogenic and likely pathogenic (P/LP) variants in well-established and multi-organ cancer predisposition genes for GC risk in a large multi-center study involving 750 GC patients, either by targeted sequencing or whole exome sequencing. We identified 45 patients (6%) with P/LP variants in ATM (17 cases), BRCA2 (10 cases), MLH1 (five cases), TP53 (three cases), BRCA1, PALB2, RAD51D and CHEK2 (two patients each), and RAD51C and PMS2 (one case each), all mutually exclusive. The P/LP variant prevalence was higher in intestinal (9.8%) than in diffuse (4.3%) or mixed GC (4.5%) (p-value=0.023), with no clear difference per mutated gene by histological subtypes. Only sixteen of the 45 variant carriers fulfilled the criteria for genetic testing of at least one cancer predisposition syndrome. Our findings indicate that multi- organ cancer predisposition genes should be included in gene panels used for investigating germline variants in GC patients, especially when there is family history of cancer but irrespective of histology subtype, as this would increase the chance of identifying patients that might benefit from prevention and targeted treatment strategies. Citation Format: Ana P. Estrada-Florez, Paul C. Lott, Luis G. Carvajal Carmona. Contribution of multi-organ cancer predisposition genes for gastric cancer risk of different histological subtypes [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C158.

Endoscopic surveillance for familial intestinal gastric cancer in low-incidence areas: An effective strategy.

While clinical practice guidelines for hereditary diffuse gastric cancer are well established, there is no consensus on the approach for familial intestinal gastric cancer (FIGC). In low-incidence gastric cancer (GC) areas such as the United States or most European countries, there are no evidence-based recommendations on endoscopic assessment in FIGC families. We aim to describe the yield of GC surveillance in these families, and to identify epidemiological risk factors for the development of GC and its precursor lesions. This is a multicenter observational study involving nine tertiary Spanish hospitals, in which all individuals fulfilling FIGC criteria who underwent endoscopic surveillance were included between 1991 and 2020. Forty-one healthy individuals of 31 families were recruited. The median number of upper gastrointestinal endoscopies per individual was 3 (interquartile range, IQR, 1-4). The median interval time between tests was 2 years (IQR 1.5-2.5), and the median follow-up was 9 years (IQR 3-14.5). In 18 (43.9%) subjects, a precursor lesion of GC was found during follow-up, and in 2 (4.9%), an early GC was identified, in which curative treatment was offered. Helicobacter pylori (Hp) infection proved to be independently associated with an increased risk of developing precursor lesions or GC, adjusted by age, gender and follow-up, with an Odds Ratio of 6.443 (1.36-30.6, P value .019). We present the first outcomes that support endoscopic surveillance with biopsies and detection of Hp in FIGC families, although the periodicity has yet to be defined.

BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.

PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Identification of a subpopulation of patients with gastric cancer responsive to PARP inhibitors.

432 Background: Treatment with PARP inhibitors (PARPi) has been approved in some tumors bearing a deficient Homologous Recombination (HR) system. Despite negative results of clinical trials conducted on the overall population of gastric cancer (GC) patients, we wondered whether a PARPi therapeutic strategy might represent a window of opportunity for a subpopulation of these patients. 7-12% of gastric cancers exhibit a mutational signature associated with HR failure, suggesting that these patients might benefit from PARPi. Methods: To analyze responsiveness to PARPi we exploited a proprietary human Gastro-Esophageal Adenocarcinoma (GEA) annotated platform of Patient-Derived Xenografts (PDXs) and PDX-derived primary cells on which we performed in vivo and in vitro experiments. Results: We selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that treatment with PARPi was effective in PDXs harbouring BRCA2 germline mutations and somatic inactivation of the second allele in a microsatellite stable background. PARPi responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency and mutational signatures efficiently stratified responder vs non-responder PDXs. A retrospective analysis on 57 GEA patients showed that those carrying BRCA2 inactivating variants had longer PFS upon platinum-based regimens (used as proxy). In 5 out of 7 BRCA2 germline mutated patients we identified the p.K3326* variant, currently classified as “benign”. However, familial history of cancer, the absence of RAD51 foci in the tumor cells and a high HR deficiency score suggest a deleterious effect for this mutation in gastric cancer. Conclusions: PARP inhibition could represent a new therapeutic perspective for BRCA2 mutated and/or high HRD score GEA patients, including familial intestinal gastric cancer patients.

Frequency of Positive Familial Criteria in Patients with Adenocarcinoma of the Esophageal-Gastric Junction and Stomach: First Prospective Data in a Caucasian Cohort.

Simple SummaryIt is well known for gastric cancer patients with subtype of diffuse histology that a proportion of patients harbour an increased familial risk. Some patients and relatives even may be detected through a genetic testing. More precise studies about the frequency of hereditary criteria in a poplation with only European ancestries for adenocarcinoma of the esophagogastric junction and stomach are missing. In current guidelines regarding genetic testing criteria not all types of stomach cancer are considered as for example patients not with subtype of diffuse histology mostly have no detectable responsible gene. The aim of the current study was to register stomach cancer patients of all different types in a certain region (Berlin, Germany) and to estimate the frequency of positive familial criteria. Patients with esophageal cancer served as comparison group as familial or hereditary background, respectively, is not significant in these patients according to current knowledge. In our study, we identified positive familial criteria in about 15% of stomach cancer patients. In regard to all different types of stomach cancer, this number almost doubled. Furthermore, one third of all registered patients in this study might have a familial or hereditary background of their disease. We therefore conclude that guidelines regarding genetic testing criteria and screening examinations should be adjusted in future.Objectives: Current prospective studies investigating the frequency of hereditary criteria in a Caucasian population for adenocarcinoma of the esophagogastric junction (AEG) and stomach (GC) are missing. Genetic testing criteria (screening criteria) for hereditary diffuse gastric cancer (HDGC) were updated in 2020, but do not address patients with intestinal histology (familial intestinal gastric cancer FIGC). Thus, we prospectively screened patients residing in Berlin newly diagnosed with AEG or GC for hereditary criteria to gain insights into the frequency of HDGC. Methods: Prospective documentation of familial/clinical parameters in patients residing in Berlin with AEG or GC over three years was conducted. Besides HDGC criteria from 2015 and revised 2020, we also documented patients fulfilling these criteria but with intestinal type gastric cancer (FIGC). Statistical analysis was performed using X2-test. Results: One hundred fifty-three patients were finally included (92 GC; male: 50 (n.s.); 61 AEG; male: 47; p = 0.007). Hereditary criteria for HDGC were detected in 9/92 (9.8%) (2015 criteria) and in 14/92 (15.2%) (2020 criteria) of GC patients (AEG: 2015 criteria 3/61 (4.9%) versus 4/61 according to 2020 criteria (6.5%)). Patients fulfilling hereditary criteria but with intestinal histology (FIGC) increased from 8.7% (2015) to 14.1%, respectively (2020) (AEG: 3.2% (2015) versus 6.6% (2020)). Hereditary criteria including intestinal histology were found in 29.3% (GC) and 13.1% (AEG) (p = 0.03) according to the 2020 criteria. Conclusions: HDGC criteria were found in 15.2% of GC patients according to the 2020 criteria. Percentage increased to 29.3% including patients with intestinal histology among the GC group, and was 13.1% in cases with AEG. These data indicate that family history seems to be of utmost importance in GC to further detect potential hereditary genetic risks. This equally applies for patients with intestinal subtype GC.

Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes

Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.

Recent advances in the pathology of heritable gastric cancer syndromes.

Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well-defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis, Li-Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.

Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives

BackgroundFamilial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic...

Hereditary cancer risk assessment: challenges for the next-gen sequencing era.

Hereditary cancer risk assessment: challenges for the next-gen sequencing era.

Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer.

Gastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer mortality. Three hereditary gastric cancer syndromes have been described; hereditary diffuse gastric cancer (HDGC), familial intestinal gastric cancer (FIGC) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Thirty per cent of HDGC families have heterozygous germline mutations in CDH1, which encodes E-cadherin. A germline truncating mutation in the gene encoding α-E-catenin (CTNNA1) was also recently discovered in a family with HDGC, but no other genes specifically predisposing to gastric cancer have been identified, leaving the majority of cases showing familial aggregation without a known genetic cause. The aim of this study was to find the putative gastric cancer predisposing gene defect in a family with HDGC that had previously been tested negative for mutations in CDH1. In this family, there were six cases of diffuse gastric cancer in two generations. Exome sequencing was applied to two affected family members. The shared variants which were predicted deleterious in silico and could not be found in databases or in a control set of over 4,000 individuals were Sanger sequenced in a third family member. Three candidate variants were identified: p.Glu1313Lys in Insulin receptor (INSR), p.Arg81Pro in F-box protein 24 (FBXO24) and p.Pro1146Leu in DOT1-like histone H3K79 methyltransferase (DOT1L). These variants and adjacent regions were screened for in an additional 26 gastric cancer patients with a confirmed (n = 13) or suspected (n = 13) family history of disease, but no other non-synonymous mutations were identified. This study identifies INSR, FBXO24 and DOT1L as new candidate diffuse gastric cancer susceptibility genes, which should be validated in other populations. Of these genes, INSR is of special interest as insulin signaling was recently shown to affect tumor cell invasion capability by modulating E-cadherin glycosylation.

Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

The prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. A series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed. CDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. CDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease.

Hereditary Diffuse Gastric Cancer: Surveillance Endoscopy is Not Enough to Save Lives

Hereditary Diffuse Gastric Cancer: Surveillance Endoscopy is Not Enough to Save Lives