Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy.
BACKGROUND
A subset of patients with diffuse gastric cancer harbor deleterious cancer-causing germline mutations in the type 1 E-cadherin (epithelial) gene (CDH1), which predisposes to the autosomal dominantly inherited hereditary diffuse gastric cancer (HDGC) syndrome. These mutations are associated with a 70% life-time risk for diffuse gastric cancer (DGC) and an additional 40% risk for lobular breast cancer in women. Management options for unaffected mutation carriers include prophylactic total gastrectomy.


METHODS
Four HDGC pedigrees from a cohort of 56 CDH1 mutation-positive families were subjected to further analysis. Cancer diagnoses, whenever possible, were verified with pathology reports and/or slides/tissue block review. Genetic counseling for family members covered the natural history of HDGC, the pros and cons of mutation testing, the lack of effective screening procedures available to CDH1 mutation-positive individuals, and the option for them of prophylactic total gastrectomy.


RESULTS
Within the 4 families, carrier testing for mutations in the CDH1 gene was carried out on 52 individuals, including 25 individuals who were positive for mutation. Prophylactic gastrectomies were performed on a total of 17 individuals from 3 of the families, including 11 first cousins from 1 of the families. Occult DGC was diagnosed in gastrectomy specimens from 13 of 17 individuals (76.5%). During follow-up questioning, each of the 11 cousins stated that the decision for the prophylactic procedure was the "right one" for them.


CONCLUSIONS
Unaffected mutation carriers from HDGC families face difficult decisions and can be assisted best through education and interactions with counseling by an informed multidisciplinary team.
Lynch
Henry T
HT
Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska 68178, USA. htlynch@creighton.edu
Kaurah
Pardeep
P
Wirtzfeld
Debrah
D
Rubinstein
Wendy S
WS
Weissman
Scott
S
Lynch
Jane F
JF
Grady
William
W
Wiyrick
Sara
S
Senz
Janine
J
Huntsman
David G
DG
D000328:Adult; D000368:Aged; D015820:Cadherins / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005743:Gastrectomy; D005817:Genetic Counseling; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D013274:Stomach Neoplasms / Q000235:genetics* / Q000523:psychology / Q000601:surgery*
D015820:Cadherins