Genetic predisposition to

gastric cancer

Anne-Marie GerdesKlinisk Genetisk Klinik

Gastric cancer and genetics

• 5-10% of patientens pos FH of GI-cancer

• 3-5% are hereditary cancer syndrome

Chun N et al. Cancer J 2012FH: Family History

Hereditary cancer syndromes increased risk of gastric cancer

Syndrome 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

Stoffel EM J Clin Oncol 2015Gaston D et al. PlosOne 2014

Moderate penetrant genes ? PALB2ATMPRSS1SDHB

Tumor cell

other mutations

2. hit

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

Van der Post RS et al. J Med Genet 2015

DGC: diffuse gastric cancerLBC: lobular breast cancerFH: family history

50% (Fitzgerald RC et al. J Med Genet 2010)

19% (Hansford A et al. JAMA Oncol 2015)

Frequency of germline CDH1 mutations

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

Navn (Sidehoved/fod) 10

New technology gene test NGS

• Genome sequencing (WGS):• Whole genome analyzed

• Exome sequencing:• All genes analyzed

• Targeteret sequencing:• Gene panels analyzed

Incidental findings

Coverage

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

13

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?

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