Hereditary Diffuse Gastric Cancer

Maori family: First described 1964: Jones Becker et al: Sporadic DGC 1994

Somatic E-Cadherin mutation

Parry Guilford: Nature 1998: Familial DGCGermline E-Cadherin mutationHDGC named in 1999

Exon

70G

T

586G

T

49-2A

C

59G

A

187C

T

190C

T

283C

T372delC

832G

A

1008G

T

1137+1G

A

1711insG

1472insA

1488del7

1588insC

1792C

T

2095C

T

2381insC

185G

T

731A

G

1018A

G

1460T

C

1710delT

1565+1G

T

2295+5G

A

2494G

A

1849G

A

1901C

T

1243A

C

1619insG

2396C

G

892G

A

1225T

C

2195G

A

2310delC

2061delTG

1779insC

1711+5G

A

1476delAG

1212delC

1134del8ins5

1064insT

687+1G

A

382delC

Missense

Deletion

Nonsense

Splice site

1391delTC

49-2A

G

1137G

A

715G

A

Sig Precursor Extracellular DomainTM Cytoplasmic

Domain1003C

T

45insT

53delC

2440-6C

G

1107delC

353C

G

41delT

Insertion

46insTGC

3G

C2T

C

377delC

515C

G531+2T

A

641T

C

753insG

808T

G

833-2A

G

1023T

G1062delG

1118C

T

1285C

T

1466insC

1507C

T1565+1G

A1565+2insT

1610delC

1682insA

1774G

A1795A

T

1876T

A1913G

A

2064delTG

2161C

G2164+5G

A

2245C

T2269G

A2276delG

2287G

T

2343A

T

2392G

A2395delC

2399delC

161 2 3 4 5 6 7 9 11 12 13 14 15108

Protein Domain

1063delT

Functional germline E-Cadherin (CDH1) mutations

actin cytoskeleton

E-cadherin

cateninsα

αβ

E-cadherin

• Dominant inheritance • Diffuse gastric cancer- signet ring cell carcinoma- linitis plastica

• 80% penetrance (advanced)

• Germline CDH1 mutation

• Rare- ~100 different mutations (published)>150 families worldwide

downregulation of 2nd CDH1allele is required for initiation

Normal mucosaCDH1 +/-

Signet ring cellcarcinoma CDH1 -/-

division withinthe epithelial plane

abnormal spindle

orientation

disrupted cell adhesion and polarity

division outof the

epithelial plane

SRC accumulation

in thelamina propria

downregulationof 2nd CDH1 allele

Adherens Junctions and Stem Cell Spindle Orientation

Signet ring cell carcinoma derives from stem cell compartment

• 2nd CDH1 allele lost• abnormal orientation of mitoticspindle

• division out of the plane• additional epigenetic changes?

Expansion andDifferentiation

differentiating progeny

Indolent T1a carcinomaGenomic InstabilityDNA damage response?Senescence?

Potentially transient

• increasing proportion ofpoorly differentiated cells

• activation of c-Src system

Invasion beyond the Mucosa

Epithelial-mesenchymalTransition

Additional mutations?

• Evaluation of a 3 generation pedigree

• Histopathological confirmation of DGC (not intestinal)

• Discussion of lifetime risk

• Multidisciplinary team (surgery, gastroenterology, pathology, nutrition, genetics)

• Begin at ~16yrs, but younger on a case by case basis

(i) 2 or more cases of GC (diffuse or unknown histotype butnot intestinal type) with at least one confirmed DGC at <50yrs age

(ii) 3 confirmed DGC independent of age

(iii) Individuals with DGC <40yrs and no family history

(iv) History of DGC and lobular breast ca, one case <50yrs

~50% of families meeting criteria (i) have a CDH1 mutation

1st or 2nd degree relatives

CDH1 mutation positive

Surveillance endoscopy Prophylacticgastrectomy

Biopsy +ve forsignet ring cells

Biopsy -ve

Repeat annually

If unwilling for surgery,preferring to delay, or <20yrs

•close nutritionalfollowup

• lobular br cascreening from 35yrs

• colon ca screeningif present in family

Age >20yrs

Invasive lobular

Invasive ductal

in situ lobular neoplasia

Right Mastectomy (300 sections)

Vanessa Blair

• 4 foci of ILC• 1 invasive ductal cancer (IDC)• 30 foci of in situ lobular neoplasia (both atypical lobular hyperplasia and lobular carcinoma in situ.

-E-cadherin expression was absent in LBC, present in IDC.

Penetrance of HDGC

0%10%20%

30%40%50%60%70%80%

90%

0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75-

age

Risk/male67%

Risk/female83%

cum

ulat

ive

risk

Pharoah et al. (2001)

• Conducted at Centre with special interest or experience of HDGC• White light, high definition endoscopy / narrow band imaging • 30 mins; careful inspection with inflation and deflation

• Biopsy any suspicion lesions• Take 6 random biopsies from the antrum, Transitional Zone,

body, fundus and cardia

• Test for H. pylori and eradicate as required (WHO class I carcinogen)

Annually or Every 6 months?? Compliance issuesFalse reasurance may delay diagnosis of invasive carcinoma

Well defined marginDistinct pallorFlatMay be best seen from a distance

(Pentagastrin stimulation)

Endoscopy

39y M: 9 mm

congo red-methylene blue

•Congo red not essential (?carcinogenic + affects fertility in mice)

•See Gut 2005 (David Shaw/Vanessa Blair et al)

Role of surveillance

~95% of CDH1 mutation carriers have multifocal T1a SRCC (signet ring cell)not detected by surveillance-probably from a young age

Surgery is initiated once focus is found

but

Foci are probably present anyway

Therefore, surveillance is being used to:

(i) detect progressive disease(ii) provide tangible evidence to the mutation carrier

to support a decision to have a gastrectomy

Charlton et al. Gut (2004)

28yrs

• Multifocal T1a foci-range -> 487; NZ mean ~100

• 0.1-10 mm diameter

• Found in practically all CDH1 mutation carriers

• Independent

• Can show TZ enrichment

Multifocal disease

Amanda Charlton, Middlemore Hospital

15yrs

Amanda Charlton, Middlemore Hospital

T2 cancer+ surrounding signet ring cellfoci

Prophylactic gastrectomy guidelines

-total gastrectomy: Roux-en-Y procedure

-no requirement for radical lymph node dissection

-esophagus transected 3-4cm above the gastroesophageal junction to ensure complete resection of gastric mucosa

15 12 9 7 6 4 4

13 11 4 2 2 0 0

15 13 9 9 8 4 2

17 8 6 2 2 0 0

Number at risk (60)

Node negative gastric cancer

Node positive gastric cancer

Node negative oesophageal cancer

Node positive oesophageal cancer

Gastrectomy for HDGC

IGCLC guideline for Centre> 25 gastrectomies annually< 5% mortality

Need follow-up for side effects

(International Gastric Cancer Linkage Consortium)

Oesophagectomy

N = 37

Total Gastrectomy

N = 23

DistalGastrectomy

N = 9

Excision of Gastric mass

N = 4

30 day mortality 0 0 0 0

Post-op stay> 3 weeks 4 (10.8%) 4 (17.4%) 2 (22.2%) 0

Anastomoticleak 1 (2.7%) 0 0 0

Genetic Counsellingand Clinical Management

J. Med. Genet. 2010; 47:436-444

Management of Hereditary Diffuse Gastric Cancer

Parry Guilford

Cancer Genetics LaboratoryUniversity of OtagoDunedin, New Zealand

• DNA sequencing of all exons and promoter

• Large deletion analysis-MLPA or array CGH

• 2 or more 1st or 2nd degree relatives with diffuse gastric cancer – one diagnosed before age 50

• 3 or more 1st or 2nd degree relatives with DGC at any age

• 25% above families have CDH1 mutationInternational Gastric Cancer Linkage Consortium(USE PARRY’S SLIDE ON SAME TOPIC)

Endoscopy

Chromoendoscopy using Congo Red dye (pH sensitive) following pentagastrin stimulation