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Hereditary diffuse gastric cancer: What the clinician should know.

ABSTRACT: Hereditary diffuse gastric cancer (HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene (CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.

SUBMITTER: Tan RY

PROVIDER: S-EPMC4569593 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Hereditary diffuse gastric cancer: What the clinician should know.

Tan Ryan Ying Cong RY Ngeow Joanne J

World journal of gastrointestinal oncology 20150901 9

Hereditary diffuse gastric cancer (HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene (CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive ann ...[more]

PMID: 26380059

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Project description:ImportanceThe E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown.ObjectiveTo assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC.Design, setting, and participantsThis cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020.Main outcomes and measuresIncidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC.ResultsAmong 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC.Conclusions and relevanceThis study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

Project description:BackgroundHereditary diffuse gastric cancer (HDGC) syndrome results most often from a mutation in the CDH1 tumor suppressor gene and confers a 56-70% lifetime risk of gastric cancer. In asymptomatic carriers HDGC is characterized by multiple foci of signet ring cancer cells (SRCC) throughout the gastric mucosa. Because SRCC foci are less than 1 mm in diameter, and often make up less than 2% of the gastric mucosa, they are undetectable on standard screening endoscopy. International consensus guidelines recommend thorough white light endoscopic gastric mapping with a systematic method for gastric biopsies. Despite a painstaking approach to gastric mapping, retrospective analyses have demonstrated a low rate of detection and poor sensitivity of standard white light endoscopy for detecting occult cancer cells. Therefore, a more sensitive cancer screening tool is needed for these high-risk patients. Confocal endoscopic microscopy (CEM) allows for real-time, in vivo histologic imaging of gastrointestinal mucosa during upper endoscopy. Clinical application has demonstrated the ability of CEM to differentiate normal mucosal cells and cancer cells.MethodsA phase II clinical trial is currently underway to compare CEM to standard endoscopic gastric mapping in an effort to reduce the false negative detection rate of SRCC in patients diagnosed with HDGC. After an upper endoscopy with gastric mapping is performed, patients will undergo probe-based CEM. The endoscopist will scan the anatomic zones of the stomach in a similar fashion to the systematic gastric mapping approach. Any abnormal areas visualized with the CEM probe will be biopsied and sent for permanent pathologic analysis. The primary endpoint is to determine if CEM affords a higher sensitivity for detection of SRCC in CDH1 germline mutation carriers compared to white light endoscopy with gastric mapping.DiscussionThis novel screening technique is expected to provide greater sensitivity for detecting occult cancer in patients with HDGC, thereby improving cancer risk-assessment and overall cancer care.Trial registrationClinicalTrials.gov NCT03648879 (registration date: August 28, 2018, clinicaltrials.gov).

Dataset Information

Hereditary diffuse gastric cancer: What the clinician should know.

Publications

Hereditary diffuse gastric cancer: What the clinician should know.

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