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Enhanced endoscopic detection of occult gastric cancer in carriers of pathogenic CDH1 variants

  • Original Article—Alimentary Tract
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Abstract

Background

Germline inactivating variants in the CDH1 tumor suppressor gene impart an elevated lifetime risk of diffuse gastric cancer. The current endoscopic surveillance method depends upon random gastric biopsies for early cancer detection.

Methods

Asymptomatic adults with pathogenic or likely pathogenic CDH1 variants referred for endoscopic gastric cancer surveillance were included in this retrospective cohort. Upper gastrointestinal endoscopy was performed according to the consensus Cambridge method, in the early period, or a systematic (Bethesda) protocol as part of an ongoing natural history study. The primary outcome measure was cancer detection.

Results

Collectively, 135 endoscopic surveillance procedures were performed in 120 patients. Twenty-six (19%, 26/135) procedures were performed using Cambridge method and 109 (81%) using the Bethesda protocol. Gastric signet ring cell carcinomas were detected in 15% (4/26) using the Cambridge method and 36% (40/109) using the Bethesda protocol (p < 0.05). Almost half (44.2%, 53/120) of patients later elected for prophylactic total gastrectomy, of whom 51 (96%, 51/53) had a signet ring cell carcinoma (T1a) discovered by histopathology. On a per endoscopy basis, the false-negative rates of detection using Cambridge method and Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively (p < 0.01).

Conclusions

Gastric cancer detection was more frequent with implementation of a systematic surveillance protocol in CDH1 variant carriers. Given the decision for prophylactic surgery is often made by patients in the context of family history and pathologic result of surveillance biopsies, we propose the Bethesda protocol offers patients an opportunity to make more informed decisions.

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References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Google Scholar 

  2. Palli D, Galli M, Caporaso NE, et al. Family history and risk of stomach cancer in Italy. Cancer Epidemiol Biomarkers Prev. 1994;3:15–8.

    CAS  PubMed  Google Scholar 

  3. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–5.

    Article  CAS  Google Scholar 

  4. Berx G, Becker KF, Hofler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat. 1998;12:226–37.

    Article  CAS  Google Scholar 

  5. Oliveira C, Pinheiro H, Figueiredo J, et al. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 2015;16:e60-70.

    Article  Google Scholar 

  6. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1:23–32.

    Article  Google Scholar 

  7. Roberts ME, Ranola JMO, Marshall ML, et al. Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.1208.

    Article  PubMed  PubMed Central  Google Scholar 

  8. van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52:361–74.

    Article  Google Scholar 

  9. Xicola RM, Li S, Rodriguez N, et al. Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria. J Med Genet. 2019;56:838–43.

    Article  CAS  Google Scholar 

  10. Lim YC, di Pietro M, O’Donovan M, et al. Prospective cohort study assessing outcomes of patients from families fulfilling criteria for hereditary diffuse gastric cancer undergoing endoscopic surveillance. Gastrointest Endosc. 2014;80:78–87.

    Article  Google Scholar 

  11. Mi EZ, Mi EZ, di Pietro M, et al. Comparative study of endoscopic surveillance in hereditary diffuse gastric cancer according to CDH1 mutation status. Gastrointest Endosc. 2018;87:408–18.

    Article  Google Scholar 

  12. Moreira L, Castells A. Surveillance of patients with hereditary gastrointestinal cancer syndromes. Best Pract Res Clin Gastroenterol. 2016;30:923–35.

    Article  Google Scholar 

  13. Moslim MA, Heald B, Tu C, et al. Early genetic counseling and detection of CDH1 mutation in asymptomatic carriers improves survival in hereditary diffuse gastric cancer. Surgery. 2018;164:754–9.

    Article  Google Scholar 

  14. Chen Y, Kingham K, Ford JM, et al. A prospective study of total gastrectomy for CDH1-positive hereditary diffuse gastric cancer. Ann Surg Oncol. 2011;18:2594–8.

    Article  Google Scholar 

  15. Hebbard PC, Macmillan A, Huntsman D, et al. Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients. Ann Surg Oncol. 2009;16:1890–5.

    Article  CAS  Google Scholar 

  16. Pandalai PK, Lauwers GY, Chung DC, et al. Prophylactic total gastrectomy for individuals with germline CDH1 mutation. Surgery. 2011;149:347–55.

    Article  Google Scholar 

  17. Kumar S, Katona BW, Long JM, et al. Endoscopic ultrasound has limited utility in diagnosis of gastric cancer in carriers of CDH1 mutations. Clin Gastroenterol Hepatol. 2020;18(505–508):e501.

    Google Scholar 

  18. Shaw D, Blair V, Framp A, et al. Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy? Gut. 2005;54:461–8.

    Article  CAS  Google Scholar 

  19. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  20. Yao K. The endoscopic diagnosis of early gastric cancer. Ann Gastroenterol. 2013;26:11–22.

    PubMed  PubMed Central  Google Scholar 

  21. Garland SN, Lounsberry J, Pelletier G, Bathe OF. How do you live without a stomach? A multiple case study examination of total gastrectomy for palliation or prophylaxis. Palliat Support Care. 2011;9:305–13.

    Article  Google Scholar 

  22. Hamilton JG, Long JM, Brandt AC, et al. Patients’ medical and psychosocial experiences after detection of a CDH1 variant with multigene panel testing. JCO Precis Oncol. 2019;3:1–14.

    Google Scholar 

  23. Fujita H, Lennerz JK, Chung DC, et al. Endoscopic surveillance of patients with hereditary diffuse gastric cancer: biopsy recommendations after topographic distribution of cancer foci in a series of 10 CDH1-mutated gastrectomies. Am J Surg Pathol. 2012;36:1709–17.

    Article  Google Scholar 

  24. de Almeida Artifon EL, Marinho FRT. Endoscopic screening for hereditary diffuse gastric cancer: one size does not fit all. Gastrointest Endosc. 2018;87:405–7.

    Article  Google Scholar 

  25. Leung WK, Wu MS, Kakugawa Y, et al. Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol. 2008;9:279–87.

    Article  Google Scholar 

  26. Barber ME, Save V, Carneiro F, et al. Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk. J Pathol. 2008;216:286–94.

    Article  CAS  Google Scholar 

  27. Charlton A, Blair V, Shaw D, et al. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut. 2004;53:814–20.

    Article  CAS  Google Scholar 

  28. Ruff S, Curtin B, Quezado M, et al. Evaluation of confocal endoscopic microscopy for detection of early-stage gastric cancer in hereditary diffuse gastric cancer (HDGC) syndrome. J Gastrointest Oncol. 2019;10:407–11.

    Article  Google Scholar 

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Funding

This study was supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute.

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Authors and Affiliations

  1. Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Bryan Franklin Curtin, Samuel Ali Schueler, Monica Passi, Theo Heller & Christopher Koh

  2. Division of Gastroenterology and Motility, Mercy Medical Center, Baltimore, MD, USA

    Bryan Franklin Curtin

  3. Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA

    Lauren Ann Gamble, Samantha Marilyn Ruff, Jonathan Matthew Hernandez & Jeremy Lee Davis

  4. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Martha Quezado & Markku Miettinen

  5. Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Grace-Ann Fasaye

Authors
  1. Bryan Franklin Curtin
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  2. Lauren Ann Gamble
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  3. Samuel Ali Schueler
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  4. Samantha Marilyn Ruff
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  5. Martha Quezado
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  6. Markku Miettinen
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  7. Grace-Ann Fasaye
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  8. Monica Passi
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  9. Jonathan Matthew Hernandez
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  10. Theo Heller
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  11. Christopher Koh
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  12. Jeremy Lee Davis
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Contributions

All the authors have contributed to and approved the final version of the manuscript. The respective roles of each author are the following: BFC, TH, CK, and JLD: study concept and design; all the authors: data analysis; all the authors: interpretation of results; BFC, LAG, SAS, and SMR: drafting the manuscript; all the authors: critical revision of the manuscript for valuable intellectual content.

Corresponding author

Correspondence to Jeremy Lee Davis.

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The authors declare no conflict of interest. The authors have no relevant personal, professional or financial disclosures.

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Curtin, B.F., Gamble, L.A., Schueler, S.A. et al. Enhanced endoscopic detection of occult gastric cancer in carriers of pathogenic CDH1 variants. J Gastroenterol 56, 139–146 (2021). https://doi.org/10.1007/s00535-020-01749-w

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  • DOI: https://doi.org/10.1007/s00535-020-01749-w

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