CDH-1 mutation and cancer
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: 361-374
Consensus Conference 2014
Surgery - recommendations
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 20- 30 – (consider family phenotype) Endoscopic surveillance not sufficient Age > 75 - consider carefully
Endoscopy
Always before ”prophylactic” operation When patients decline operation In clinically defined HDGC families without CDH1
mutation Multiple (30) biopsies (5 x 6 regioner)Purpose1. Already invasive cancer ? 2. If a microscopic focus of SRCC is shown –
motivation for surgery
Family A - proband
32 – year old man SRCC of the stomachLaparotomy (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
Family A
M+ M+ M+M+
42†+ 3 Cousins with gastric cancer
2 died young
45 41 37 3932 42
Do not want test
M÷ M÷†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)
Familie B - proband 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.1565+3insTT i exon 10 Uncertain effect – testet and found to be pathogenic
M+
M+M+M+
M+ M+ M+
M+
M+
M+
M+M+
M+
M - M-
M-M-M-
M-
M -
† † †
†††
†
: Prophylactic gastrectomy
Family B
Proband
9 asymptomatic members testet positive :
5 total gastrectomy in DK1 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)
M+
SRCC: Microscopic focus of Signet Ring Cell Carcinoma (T1A)
Prophylactic total gastrectomy in 9 asymptomatic CDH1 mutation positive members
Family/member Mutation
Endoscopic findings
Stomach pathology
Examined lymph nodes/malignant
Postop. Complications
Postop. LOS
Family A c.602_603delCT Exon 5
45 y - male Normal Invasive SRCC T3N0M0
12/0 None 8
41 y - male 1 SRCC 12 SRCC 22/0 None 6
Family B c.1565+3insTT Exon 10
26 y - female Normal 5 SRCC 16/0 None 7
39 y - female Normal/2 SRCC after revision
82 SRCC 18/0 None 7
52 y - female Normal
16 SRCC 16/0 None 7
48 y – male 1 SRCC 35 SRCC 13/0 None 7
29 y - male Normal 72 SRCC 41/0 None 6
Family C c.1562delT Exon 10
40 y - female Normal Normal 24/0 None 9
43 y - male Normal 50 SRCC 16/0 None 6
Bardram L, Hansen TVO, Gerdes AM et al . Familial Cancer 2014; 13: 231-42
Weight before and after gastrectomyKg
Weightloss 10-25 % at 1 year
T3 cancer + chemo
Before After40
50
60
70
80
90
100
110
Weight and QOL after prophylactic gastrectomy 32 patients - multicenter study
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 2014.
% weight loss
Physical function scorePhysical health score
Timing of the operation
Recommended at age 20-30 Consider familial ”phenotype” Age > 75 - consider carefully
What about pregnancy delivery of healthy child documentedartificial fertilization after egg sorting
26 year old woman in Family B
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
Breast Cancer 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
www.nostomachforcancer.org
”NO STOMACH FOR CANCER”