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
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

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.
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

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

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
Navn (Sidehoved/fod) 10

11. 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? 13

14. 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