The gene codes for the protein E-cadherin (epithelial) Many subtypes of cadherins (= calcium-dependent adhesion) Deactivating mutations are pathogenic Loss of E-cadherin expression

J Med Genet 2015; 52: Consensus Conference 2014

 CDH 1 mutation positiv – total gastrectomy  D1 lymphnode resection (pos lympnodes in T1 a 2-6% in T1 b 17-25%)  Ensure proximal and distal margins to be without gastric mucosa  At age – (consider family phenotype)  Endoscopic surveillance not sufficient  Age > 75 - consider carefully

 Always before ”prophylactic” operation  When patients decline operation  In clinically defined HDGC families without CDH1 mutation  Multiple (30) biopsies (5 x 6 regioner) Purpose 1. Already invasive cancer ? 2. If a microscopic focus of SRCC is shown – motivation for surgery

 32 – year old man SRCC of the stomach Laparotomy (GEA): Carcinose + liver metastases Died few weeks postoperatively with unclear CNS symptoms (carcinomatosis o.p)  Father died of gastric cancer 42 years old  3 cousins of the father also had gastric cancer at an early age  A patogenic CDH – 1 mutation (2 – bp deletion in exon 5) was shown

42 † + 3 Cousins with gastric cancer 2 died young Do not want test † Probanden † Died of gastric cancer Do not want operation or control Prophylactic gastrectomy 5 siblings: 3 positive 1 negative 1 no test 2 operated 1 cousin : negative (married to the probands sister)

 44 year old man subtotal gastrectomy and chemotherapy for T2N2M0 SRCC. Metastases to neck lymphnodes 3 months later † 45 år  Grandfather died of gastric cancer  Mother died at 27 years with peritoneal carcinosis  Mothers brother and sister died of gastric SRCC – 51 and 68 years old  Brother died of gastric SRCC - 49 år CDH 1 mutation: c insTT i exon 10 Uncertain effect – testet and found to be pathogenic

††† †† † † : Prophylactic gastrectomy Proband 9 asymptomatic members testet positive : 5 total gastrectomy in DK 1 probably operated in Italy 1 had disseminated disease when testet (had refused the test a year earlier) 2 are 19 and 20 years. (one living in Sweden)

SRCC: Microscopic focus of Signet Ring Cell Carcinoma (T1A) Bardram L, Hansen TVO, Gerdes AM et al. Familial Cancer 2014; 13:

Kg Weightloss % at 1 year T3 cancer + chemo

The Impact of Prophylactic Total Gastrectomy on Health-Related Quality of Life: A Prospective Cohort Study. Worster, Elizabeth; Liu, Xinxue; Richardson, Susan; Hardwick, Richard; Dwerryhouse, Sarah; Caldas, Carlos; Fitzgerald, Rebecca Annals of Surgery. 260(1):87-93, July % weight loss Physical function scorePhysical health score

 Recommended at age  Consider familial ”phenotype”  Age > 75 - consider carefully  What about pregnancy  delivery of healthy child documented  artificial fertilization after egg sorting

 Was early pregnant when testet positive  Chose abortion - in order to proceed with gastrectomy immediately (grandmother died at age 27 of dessiminated cancer)  3 years later : Delivery of healthy child (mutation negative)  Had artificial fertilization after egg sorting  Prophylactic mastectomy a week ago (16 months after delivery)- 31 year old

 Lobular breast cancer  Annual MRI 3 women in family B: One had a small invasive cancer found by MRI – multiple LBC foci found in the resected specimen Had subsequent prophylactic bilateral mastectomy: Multiple foci of LBC Two had bilateral prophylactic mastectomy: No malignancies Whole specimen not examined for microscopic LBC foci Not sufficient evidence for recommending prophylactic mastectomy