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 increased risk of gastric cancer Genes Hereditary diffuse gastric cancer (HDGC) CDH1, CTNNA1, MAP3K6 Lynch syndrome (HNPCC) MLH1, MSH2/6, PMS2 Familial adenomatous polyposis (FAP) APC Li-Fraumeni syndrome TP53 Juvenile polyposis SMAD4, BMPR1A Peutz-Jeghers syndrome STK11 Hereditary breast-ovarian cancer (HBOC) BRCA1/2 Moderate penetrant genes ? PALB2 ATM PRSS1 SDHB Stoffel EM J Clin Oncol 2015 Gaston D et al. PlosOne 2014

2. hit Tumor cell other mutations

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

Diagnostic criteria for HDGC Different versions. Criteria for gene test: 2 or more cases of gastric cancer in 1° and 2° relatives and at least one DGC 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 cleft lip/palate in DGC patient Signet ring cell morphology DGC: diffuse gastric cancer LBC: lobular breast cancer FH: family history Van der Post RS et al. J Med Genet 2015

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

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) Other modifiers (genes, lifestyle) Incidence in population Hansford S et al. JAMA Oncol 2015

New technology gene test NGS Genome sequencing (WGS): Whole genome analyzed Exome sequencing: All genes analyzed Targeteret sequencing: Gene panels analyzed Incidental findings Coverage Navn (Sidehoved/fod) 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

Incidental findings – good or bad? High or low disease risk Uncertainty about size of disease risk Disease prevention/treatment possible? Improved survival? At what age will disease be diagnosed? Can the patient actively reduce risk? Family members? Genetic discrimination? 13

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