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Genetic predisposition to gastric cancer

Genetic predisposition to gastric cancer. Anne-Marie Gerdes Klinisk Genetisk Klinik. Gastric cancer and genetics. 5-10% of patientens pos FH of GI-cancer 3-5% are hereditary cancer syndrome. FH: Family History. Chun N et al. Cancer J 2012. Hereditary cancer syndromes

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Genetic predisposition to gastric cancer

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  1. Genetic predisposition to gastric cancer Anne-Marie Gerdes Klinisk Genetisk Klinik

  2. Gastric cancer and genetics • 5-10% of patientens pos FH of GI-cancer • 3-5% are hereditary cancer syndrome FH: Family History Chun N et al. Cancer J 2012

  3. Hereditary cancer syndromes increased risk of gastric cancer Moderate penetrant genes ? PALB2 ATM PRSS1 SDHB Stoffel EM J Clin Oncol 2015 Gaston D et al. PlosOne 2014

  4. 2. hit Tumor cell other mutations

  5. Genetic testing Mutation identified: • Diagnostic • Treatment • Predictive genetic testing family members: • -mutation: population cancer risk • +mutation: high cancer risk and follow up Mutationen not identified: • pedigree basis for risk assessment • follow up close relatives

  6. Diagnostic criteria for HDGC • Different versions. • Criteriafor gene test: • 2 or more cases of gastric cancer in 1° and 2° relatives and at leastoneDGC • One case of DGC <40 yrs • Personal or FH of DGC and LBC <50 yrs • Consider gene test: • Bilateral LBC or FA with 2 or more LBC <50 yrs • Personal or FH of cleftlip/palate in DGC patient • Signet ring cellmorphology DGC: diffuse gastric cancer LBC: lobular breast cancer FH: family history Van der Post RS et al. J Med Genet 2015

  7. Frequency of germline CDH1 mutations 50%(Fitzgerald RC et al. J Med Genet 2010) 19%(Hansford A et al. JAMA Oncol 2015)

  8. Lifetime risk of cancer at 80 yrs pathogenic germline CDH1 mutations • 70% DGC ♂ (59-80) • 56% DGC ♀ (44-69) • 42% LBC ♀ (23-68) • ? CRC and other cancers • Penetrance dependent of: • Selection (clinic vs. population) • Othermodifiers(genes, lifestyle) • Incidence in population Hansford S et al. JAMA Oncol 2015

  9. New technology gene test NGS • Genome sequencing (WGS): • Whole genome analyzed • Exome sequencing: • All genes analyzed • Targeteret sequencing: • Gene panels analyzed Incidental findings Coverage 10

  10. New technology – more dilemmas • Pathogenic mutation • Normal result • Variant of unknown significance (VUS) • Mutations in other disease causing genes not related to patients symptoms (incidental findings) • Mutations in genes not related to diseases

  11. Incidental findings – good or bad? • High or lowdiseaserisk • Uncertaintyaboutsize of diseaserisk • Diseaseprevention/treatmentpossible? • Improvedsurvival? • At what age willdiseasebediagnosed? • Can the patient actively reducerisk? • Family members? • Geneticdiscrimination? 13

  12. Therefore we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles. Hansford S et al. JAMA Oncol 2015

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