Download Gastric cancer and genetics

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
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
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%
19%
(Fitzgerald RC et al. J Med Genet 2010)
(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
Incidental findings
Coverage
• Exome sequencing:
• All genes analyzed
• Targeteret sequencing:
• Gene panels analyzed
Navn (Sidehoved/fod)
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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
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Disease prevention/treatment possible?
Improved survival?
At what age will disease be diagnosed?
Can the patient actively reduce risk?
• Family members?
• Genetic discrimination?
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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