Familial Non-Hereditary Gastric Cancer: Diagnosis, Management, Molecular Characteristics and Future Perspective

Authors

Carlos Pardo

Irina Luzko

Joaquín Castillo-Iturra

Elisa Cantú-Germano

Leticia Moreira

Doi

10.3390/cancers17193209

PMID: 24816255 · DOI: 10.3390/cancers17193209 · Journal: Cancers (2025)

TL;DR

A narrative review of familial non-hereditary gastric cancer (FNHGC) — families with two or more gastric cancer (GC) cases in first- or second-degree relatives but no identifiable high-penetrance germline mutation (i.e., no CDH1, CTNNA1, Lynch, GAPPS, Li–Fraumeni, or other defined syndrome). The authors synthesize epidemiologic, molecular, and clinical evidence to argue that FNHGC is multifactorial: H. pylori-driven chronic gastritis is the dominant initiating insult, layered with shared environment (high-salt diet, smoking), low-penetrance polymorphisms (DNA-repair, inflammation), and epigenetic field defects (notably somatic CDH1 promoter hypermethylation). Molecular profiling of FNHGC tumors shows enrichment for microsatellite instability (MSI), recurrent somatic hits in TP53, RHOA, and DNA-repair genes, and candidate predisposition variants in CTNND1, DOT1L, INSR, and FBXO24. Current management hinges on multigene-panel testing to rule out hereditary syndromes, endoscopic surveillance, and aggressive H. pylori eradication.

Cohort & data

  • No primary cohort. This is a narrative literature review; no new sequencing or patient data are generated.
  • Cancer focus: STAD (gastric adenocarcinoma) — both intestinal (Lauren intestinal-type, including familial intestinal gastric cancer / FIGC) and diffuse (HDGC-like, mutation-negative).
  • Search strategy: PubMed and Scopus, English-language studies from the prior 15 years, terms ("familial" OR "non-hereditary") AND ("gastric cancer" OR "stomach cancer"; hereditary-diffuse-gastric-cancer-like). No formal quality appraisal (qualitative synthesis only).
  • Key cited primary cohorts (not re-analyzed): the Carvalho et al. 2021 FIGC cohort (50 Italian FIGC probands vs. Portuguese sporadic intestinal GC controls); Kakiuchi et al. 2014 diffuse GC RHOA series (n=87); the TCGA gastric adenocarcinoma molecular classification (EBV / MSI / CIN / GS).

Key findings

  • FNHGC accounts for the majority of familial GC. ~10% of all GC shows familial clustering; only ~1–3% of all GC is explained by known high-penetrance germline syndromes, leaving the remainder (FNHGC) without an identified Mendelian cause PMID:24816255.
  • H. pylori + family history is multiplicative. H. pylori-positive individuals with a first-degree GC relative have ~5-fold higher odds of GC vs. uninfected individuals without family history (Shin et al. 2010, cited).
  • H. pylori eradication in family-history carriers reduces GC incidence by 55%. In a landmark RCT (Choi et al. 2020), asymptomatic H. pylori carriers with a family history of GC had 0.8% vs. 2.9% GC over 9 years after eradication vs. persistent infection.
  • FIGC tumors are enriched for MSI. In Carvalho et al. 2021, ~38% (19/50) of FIGC tumors were microsatellite-unstable — a significantly higher proportion than in matched sporadic intestinal GC controls. FIGC tumors also carried higher overall somatic mutation burden.
  • Recurrent somatic drivers in FIGC include TP53, BRCA2, ATM, FHIT, MSH6, and CTNNA1, with TP53 and FHIT alterations seldom seen in matched sporadic intestinal GCs.
  • TP53 risk-associated polymorphisms enriched in FIGC. Over half (26/50) of FIGC probands carried common risk variants of TP53, vs. only ~11% (4/38) of sporadic comparators (Carvalho et al. 2021).
  • Somatic CDH1 promoter hypermethylation phenocopies germline loss. ~17% (5/28) of CDH1-mutation-negative familial GC tumors show CDH1 promoter methylation, and ~9% show CDH1 LOH — providing a somatic/epigenetic route to E-cadherin loss in HDGC-like families without germline CDH1 variants.
  • RHOA hits are shared between sporadic and familial diffuse GC. Somatic RHOA mutations occur in ~25% (22/87) of diffuse GCs overall (Kakiuchi et al. 2014), and a germline RHOA p.R129W variant segregated in one Korean HDGC family with increased GTP-binding and perturbed YAP1 signaling in functional assays.
  • Candidate FNHGC predisposition genes identified by germline exome/WGS of CDH1-negative families: DOT1L (histone methyltransferase; p.Pro1146Leu missense in a Finnish HDGC family), INSR, FBXO24 (Donner et al. 2015), and CTNND1 (Herrera-Pariente et al. 2024 — germline biomarker for early-onset GC, disrupts cell–cell adhesion).
  • No germline CDH1 epimutation found. Yamada et al. screened 22 familial/early-onset GC patients and detected no germline monoallelic CDH1 promoter hypermethylation, ruling out germline CDH1 epimutation as a major FNHGC mechanism (contrast Lynch syndrome MLH1 epimutations).
  • First-degree relatives carry frequent precursor lesions. Endoscopic screening of healthy GC-patient relatives found gastric intestinal metaplasia in 44% and low-grade dysplasia in 7%; FIGC-criteria surveillance studies report ~50% of patients developing precursor lesions over follow-up.
  • TCGA molecular subtypes (EBV / MSI / CIN / GS) do not form an FNHGC-specific class. Familial cases are distributed across canonical TCGA subtypes; FIGC enriches MSI, mutation-negative HDGC-like cases tend toward genomically stable (GS) with RHOA hits, and intestinal-type familial tumors otherwise track CIN.

Genes & alterations

  • CDH1 — germline loss-of-function defines HDGC. In mutation-negative HDGC-like families, ~17% of tumors show somatic CDH1 promoter hypermethylation and ~9% show LOH, and H. pylori-induced IL-1β can drive somatic CDH1 promoter methylation in gastric epithelial cells, phenocopying germline loss.
  • CTNNA1 — second-most-common HDGC gene (germline); also a recurrent somatic variant in FIGC tumors per Carvalho et al.
  • CTNND1 — newly proposed germline predisposition gene for early-onset GC (Herrera-Pariente et al. 2024); disrupts cell–cell interactions, potentiates motility/metastasis. Candidate explanation for a subset of FNHGC.
  • TP53 — germline drivers define Li–Fraumeni syndrome; in FNHGC, common risk-associated TP53 polymorphisms are enriched (26/50 FIGC vs. 4/38 sporadic), and somatic TP53 mutations recur in FIGC tumors uncommonly seen in matched sporadic intestinal GC.
  • RHOA — somatic gain-of-function hotspots (e.g., recurrent in ~25% of diffuse GC) and a family-specific germline p.R129W variant with elevated GTP-binding and altered YAP1 signaling.
  • DOT1L — germline missense p.Pro1146Leu in a CDH1-negative HDGC family; histone methyltransferase implicated in H3K79 methylation changes in familial gastric tumors.
  • INSR, FBXO24 — additional rare germline candidate variants from a Finnish HDGC exome study (Donner et al. 2015).
  • FHIT — fragile-site tumor suppressor with germline and somatic variants observed uniquely in FIGC vs. sporadic intestinal GC.
  • Lynch syndrome MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM) — germline loss confers Lynch-syndrome GC risk; somatic MLH1 promoter hypermethylation underlies many MSI-high familial intestinal tumors.
  • GAPPS APC promoter 1B, Peutz–Jeghers STK11, juvenile polyposis BMPR1A / SMAD4, FAP / MUTYH-polyposis (APC, MUTYH), HBOC (BRCA1, BRCA2, PALB2, ATM, BRIP1) — must be ruled out before FNHGC labeling. Standard multigene panel for GC includes all of the above plus CDH1, CTNNA1, TP53, and others.
  • Low-penetrance / GWAS susceptibility loci — PSCA, MUC1, PLCE1, PRKAA1, and DNA-repair / xenobiotic-metabolism variants (XRCC1, GSTM1-null) confer individually small risk increments; clustering in a single family may explain part of familial aggregation.
  • Pro-inflammatory polymorphisms — IL1B, TNF, IL10 — high-responder cytokine alleles amplify H. pylori-driven atrophic gastritis and intestinal metaplasia, increasing GC risk.
  • RASSF1, LOX — promoters frequently methylated long before cancer develops in H. pylori-affected stomachs (“epigenetic field defect” markers).
  • KDM4B / PTGS2 / CDKN1A axis — H. pylori upregulates the histone demethylase KDM4B (JMJD2B) and drives H4 acetylation at the CDKN1A (p21) promoter, activating PTGS2 (COX-2) and contributing to gastric carcinogenesis.

Clinical implications

  • Genetic counseling and multigene panel testing first. Any family with two or more first-/second-degree GC cases (especially with onset <50 or diffuse histology) warrants referral; the recommended GC panel covers CDH1, CTNNA1, APC (incl. promoter 1B), ATM, BMPR1A, BRCA1/2, BRIP1, EPCAM (E8–E9 deletion), MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, SMAD4, STK11, and TP53.
  • No prophylactic-surgery indication in FNHGC. Unlike pathogenic CDH1 carriers (for whom prophylactic total gastrectomy at age 20–40 is standard), mutation-negative families are managed with surveillance, not surgery.
  • Endoscopic surveillance protocols.
    • HDGC-like CDH1-negative families: high-quality EGD every 1–2 years with multiple random biopsies (per IGCLC).
    • FIGC families: EGD from ~age 40 (earlier if early-onset cases in family), every 2–3 years, with Sydney-protocol biopsies and OLGA/OLGIM histologic staging.
  • H. pylori test-and-treat in all first-degree relatives is the single highest-yield preventive intervention; eradication reduced GC by 55% in family-history carriers in a landmark RCT.
  • Lifestyle modification. Counsel relatives on reducing salt-preserved foods, increasing fresh produce, smoking cessation, and moderate alcohol.
  • Molecular subtype may guide therapy. MSI-high familial tumors (enriched in FIGC) are candidates for PD-1 immunotherapy (extrapolated from unselected GC trials — no RCTs in familial cohorts yet); RHOA-activated diffuse tumors may be susceptible to Rho/ROCK or YAP1-pathway inhibitors (preclinical hypothesis only).
  • MSI / EBV status should be confirmed by standard biomarker assays (MMR IHC, MSI-PCR or NGS-based MSI, EBV ISH) before clinical decisions.

Limitations & open questions

  • Narrative review without formal quality appraisal — the authors explicitly caution that conclusions should be interpreted with caution; no systematic-review methodology was applied.
  • No single causative gene for FNHGC. Despite two decades of sequencing, the majority of FNHGC families have no identifiable germline driver; candidate genes (CTNND1, DOT1L, INSR, FBXO24, germline RHOA p.R129W) are family-specific and await external validation in large independent cohorts.
  • MSI / CDH1-methylation prevalence estimates are derived from single cohorts (FIGC Carvalho 2021 for MSI; small HDGC-like series of n=28 for CDH1 methylation/LOH) and are not directly compared with matched sporadic diffuse controls. Generalizability across regions and histologies is uncertain.
  • Polygenic risk scores (PRS) for GC are not yet clinically actionable — small per-variant effect sizes, limited ancestry portability, and no validated integration with environmental exposures (H. pylori, diet, smoking).
  • Epigenetic field defects in normal mucosa of FNHGC relatives are suggestive but not yet a validated screening biomarker; methylation-fingerprint and circulating-miRNA assays (e.g., the miR-18a/miR-21/miR-421 plasma signature) remain investigational.
  • No RCT-grade evidence for PD-1 immunotherapy specifically in MSI-high or EBV-positive familial GC cohorts; current recommendations are extrapolated from unselected GC trials.
  • Microbiome contributions beyond H. pylori (e.g., post-eradication gastric flora, cagA-strain differences) are unresolved.

Citations from this paper used in the wiki

  • “approximately 10% shows familial clustering with only a minority explained by known hereditary syndromes” — abstract / introduction.
  • “~38% (19/50) of FIGC tumors were microsatellite instable (MSI), a significantly higher proportion than in sporadic cases” — Section 5.1, citing Carvalho et al. 2021.
  • “Over half (26/50) of FIGC individuals carried common risk-associated variants of TP53 … compared to only ~11% (4/38) of sporadic cases” — Section 5.1.
  • “Somatic CDH1 promoter hypermethylation has been observed in ~17% (5/28) of these tumors and CDH1 loss-of-heterozygosity in ~9%” — Section 5.1, derived from familial HDGC cohorts.
  • “somatic RHOA mutations in ~25% (22/87) of diffuse GCs overall” — Section 5.1, citing Kakiuchi et al. 2014.
  • “eradication of H. pylori in asymptomatic carriers reduced subsequent GC incidence by 55%” / “0.8% vs. 2.9% over 9 years” — Section 4.1, citing Choi et al. 2020.
  • “5-fold higher odds of GC in H. pylori-positive individuals with a first-degree relative affected” — Section 4.1, citing Shin et al. 2010.
  • “gastric intestinal metaplasia in 44% and low-grade dysplasia in 7% of relatives” — Section 4.2, citing Dong et al. 2022.
  • “Donner et al. … a DOT1L missense variant (p.Pro1146Leu) in a CDH1-negative diffuse GC family” — Section 5.2, citing Donner et al. 2015.
  • “Herrera-Pariente et al. identified CTNND1 as a germline biomarker for the predisposition for early-onset gastric cancers” — Section 5.3.
  • “germline RHOA mutation (p.R129W) segregating in one HDGC family … increased GTP-binding and perturbed downstream YAP1 signaling” — Section 5.3, citing Kakiuchi et al. 2014.
  • “Modern GC gene panels include CDH1, CTNNA1, APC (including variants in promotor 1B), ATM, BMPR1A, BRCA1, BRCA2, BRIP1, EPCAM (E8–E9 deletion), MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, SMAD4, STK11 and TP53” — Section 6, citing Carballal et al. 2024.

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