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”