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Original research
Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives
  1. Joana Carvalho1,2,
  2. Patricia Oliveira1,2,
  3. Janine Senz3,4,
  4. Celina São José1,2,
  5. Samantha Hansford3,4,
  6. Sara Pinto Teles1,2,
  7. Marta Ferreira1,2,
  8. Giovanni Corso5,6,
  9. Hugo Pinheiro2,7,
  10. Diana Lemos8,
  11. Valeria Pascale9,
  12. Franco Roviello9,10,
  13. David Huntsman3,4,11,
  14. Carla Oliveira1,2,12
  1. 1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  2. 2Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
  3. 3Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
  4. 4Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
  5. 5Division of Breast Surgery, European Institute of Oncology IRCCS, Milan, Italy
  6. 6Department of Oncology and Onco-Hematology, University of Milan Faculty of Medicine and Surgery, Milan, Italy
  7. 7Department of Internal Medicine, Tâmega e Sousa Hospital Center, Penafiel, Portugal
  8. 8European Bioinformatics Institute, Cambridge, Cambridgeshire, UK
  9. 9Department of Medical, Surgical Sciences and Neurosciences Section of General Surgery and Surgical Oncology, University of Siena, Siena, Toscana, Italy
  10. 10Istituto Toscano Tumori, University of Siena, Siena, Toscana, Italy
  11. 11Genetic Pathology Evaluation Centre, University of British Columbia and Vancouver General, Vancouver, British Columbia, Canada
  12. 12Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal
  1. Correspondence to Dr Carla Oliveira, Universidade do Porto Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal; carlaol{at}


Background Familial 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 causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern.

Methods Normal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts.

Results The most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06).

Conclusion This study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels.

  • cancer: gastric
  • molecular genetics
  • clinical genetics
  • diagnostics
  • evidence based practice

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  • JC and PO contributed equally.

  • DH and CO contributed equally.

  • Contributors JC: designed the study, collected, analysed and interpreted the data, wrote the initial draft of the manuscript including the text, figures and tables, and submitted the manuscript. PO: designed the study, performed bioinformatics and statistical analyses, interpreted the data, and wrote the initial draft of the manuscript including the text, figures and tables. JS, SH: performed the next-generation sequencing analyses. CSJ, SPT: validated the next-generation sequencing data. MF: participated in the bioinformatics analysis. GC: participated in the collection of patient material, collected and compiled the family history data. HP: helped with the next-generation sequencing analyses. DL: worked on the bioinformatics analyses. VP: participated in the collection of family history data. FR: sought institutional approval, performed the clinical evaluation and recruitment of patients, and collected patient material and family history data. DH: designed the gene panel sequencing, coordinated the next-generation sequencing, obtained funding and critically reviewed the manuscript. CO: had the original idea and designed the study, coordinated the study, interpreted the data, sought institutional approval and funding, critically reviewed the manuscript, and is responsible as guarantor for the overall content.

  • Funding IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology. This work has been financed by (1) FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of the following projects: (1.1) 'Institute for Research and Innovation in Health Sciences' (POCI-01-0145-FEDER-007274) and (1.2) 3DChroMe (POCI-01-0145-FEDER-30164); (2) Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) for the following projects: (2.1) NORTE-01-0145-FEDER-000029 and (2.2) DOCnet (NORTE-01-0145-FEDER-000003); (3) 'NSFC - No Stomach for Cancer': 'Defining the Contribution of Mutations in CDH1 Non-Coding Regions and Other Known Susceptibility Genes to Hereditary Gastric Cancer'; (4) FCT Fellowships: SFRH/BPD/86543/2012 to JC; SFRH/BPD/89764/2012 to PO; SFRH/BPD/79499/2011 to HP; and SFRH/BD/140796/2018 to CSJ; and (5) POCI and Programas Operacionais Regionais de Lisboa e do Algarve e pela Fundação para a Ciência e a Tecnologia, Project GenomePT - Laboratório Nacional para a Sequenciação e Análise de Genomas (22184).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Informed consent was obtained from all patients, and the study was approved by the local institutional review boards.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.