Maori family: First described 1964: Jonesconference.co.nz/files/docs/ross roberts 9.55 tues.pdf ·...
Transcript of Maori family: First described 1964: Jonesconference.co.nz/files/docs/ross roberts 9.55 tues.pdf ·...
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