molecular pathology of gastric canceracmcb.es/files/425-1495-document/carneiro-3-17feb11.pdf ·...
TRANSCRIPT
![Page 1: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/1.jpg)
Molecular Pathologyof Gastric Cancer
Fátima CarneiroIPATIMUP & FMUP/HSJ
Porto, Portugal
![Page 2: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/2.jpg)
![Page 3: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/3.jpg)
Twenty europeans countries with the highest incidence of gastric cancer
Portugal
![Page 4: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/4.jpg)
Types and sub-types of gastric carcinoma
•Adenocarcinoma•Adenosquamous carcinoma•Anaplastic carcinoma•Blue cell carcinoma•Carcinoma with lymphoid stroma•Carcinoma simplex•Desmoplastic carcinoma•Differentiated carcinoma•Diffuse carcinoma•Expanding carcinoma•Glandular carcinoma•Infiltrative carcinoma•Intestinal carcinoma•Intestinal cell type carcinoma•Linitis plastica•Lymphoepithelial carcinoma•Lymphoepithelioma-like carcinoma•Mixed carcinoma•Medullary carcinoma withlymphoid stroma
•Mucinous adenocarcino-ma•Mucoid carcinoma•Mucous cell type carcinoma•Nonglandular carcinoma•Papillary adenocarcinoma•Parietal cell carcinoma•Poorly-differentiated adenocarcinoma•Pyloric-cardiac cell carcinoma•Scirrhous carcinoma•Signet-ring cell carcinoma•Small cell carcinoma•Solid carcinoma•Solid medullary type•Squamous cell carcinoma•Tubular adenocarcinoma•Types I, II, III and ]IVof Goseki et al.•Unclassified carcinoma•Undifferentiated carcinoma
•Localization •Histotype
Ancient times 1800 Present day
Cancer of distal stomach (non-cardia)
Cancer of proximal stomach (cardia)
Incide
nce
Changing epidemiology
Morphologic heterogeneity
![Page 5: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/5.jpg)
![Page 6: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/6.jpg)
![Page 7: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/7.jpg)
METAGENOMICS
![Page 8: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/8.jpg)
The stomach displays a diverse microbiota when H. pylori is absent or low in abundance
Resident or transient populations of ingested microbes??
Stomach H. pylori -
Stomach H. pylori +
Andersson et al., PLoS ONE 2008
![Page 9: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/9.jpg)
• Helicobacter pylori infection• Diet• Smoking
Environment(Epi)Genetic alterations
Gastriccancer
Gene-environment interaction
Risk of gastric cancer developmentH. pylori virulent genotypes 15 to 17IL-1 gene polymorphism 3.3H. pylori virulence & IL-1B polymorphism 87
Machado et al. Gastroenterology 121: 823, 2001 Figueiredo et al, JNCI 94: 1680, 2002
• Polymorphisms: Mucin genes; Pro-inflammatory genes
• Mutations in “low” or “high”penetrant genes
Familial aggregation
![Page 10: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/10.jpg)
Sporadic cancer
Hereditary cancer
Morphology
Molecular pathology
![Page 11: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/11.jpg)
Intestinal (glandular) carcinoma Diffuse (isolated cell-type) carcinoma
• Elderly patients, mainly males• Decreasing incidence everywhere• Blood-born metastases
• Young patients, mainly females• Familial/hereditary conditioning• Dissemination to the peritoneum
![Page 12: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/12.jpg)
CIN (Chromosomal instability)-Aneuploidy# 3p, 7q, 13q (LOH)# 6q (LOH)# 1q, 5q, 17p (LOH)RAS (overexpression/mutation)ERBB-2 (amplification)TPR-MET (rearrangement)c-MET (6.0 Kb mARN)EGF (overexpression)TGF-a (overexpression)
p 53 (LOH, mutation)APC (LOH, mutation)DCC (LOH)p 16 (hypermethylation)
MSI (Microsatellite Instability)
S-Tn, T, S-TCDw75, S-LexLaminin, collagen IVu-PA, Cat-D NM 23 (loss)CD 44 (variants)
Diploidy# 3p, 7q, 13q (LOH)# 6q (LOH)
c-MET (6.0 Kb mRNA)
p 53 (LOH, mutation)
TGF-ß (overexpression)
K-SAM (amplification)E-cadherin (loss/mutation)
S-Tn, T, S-TCDw75, S-Lex
NM 23 (loss)CD 44 (variants)
Intestinal (glandular) carcinoma Diffuse (isolated cell) carcinoma
![Page 13: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/13.jpg)
ERBB-2
PT NM LMMucosa
ERBB-2 amplification in intestinal carcinoma
David L, Seruca R, Nesland J, Soares P, Sansonetty F, Holm R, Borresen AL,Sobrinho-Simões M: c-erbB-2 expression in primary gastric carcinomas and their metastases. Mod Pathol 5:384, 1992
![Page 14: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/14.jpg)
Blood born metastases Poor prognosis
ERBB-2 amplification in intestinal carcinoma
David L et al; Mod Pathol 5:384, 1992Barros-Silva J et al; Br J Cancer 100: 487,2009
ERBB-2In gastric carcinoma
ToGA TrialERBB2 overexpression in 22% of advanced gastric cancersSignificantly improved survival with trastuzumab
ASCO 2009 (LBA 4509)
ERBB-2
Prognostic factor YES (56%)(about 40 studies) NO (44%)
![Page 15: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/15.jpg)
a
3’-UTR EGFR A13 REPEAT
20/63 (31.7%)
EGFR mutations in sporadic gastric carcinoma
3’-UTR EGFR A13 REPEAT
EGFR mutations 2/77 cases
EGFR amplification 4/30 cases
![Page 16: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/16.jpg)
15-30% of the cases
Peltomäki P et al. Cancer Res 53:5853, 1993Seruca R et al. Int J Cancer 64:32, 1995Santos NR et al. Gastroenterology 110:38, 1996
Microsatellite Instability (MSI) in gastric cancer
![Page 17: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/17.jpg)
Survival of patients
Multivariate analysis• Staging (pTNM) (p< 0.0008)• Venous invasion (p= 0.004)• Histological classification (p=0.08)• Microsatellite instability (p=0.04)
Seruca R et al. Int J Cancer 64: 32, 1995Santos N et al. Gastroenterology 110: 38, 1996 Oliveira C et al. Am J Pathol 153: 1211, 1998
MSI is a molecular marker of good prognosis
in sporadic gastric cancer
Univariate analysis
![Page 18: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/18.jpg)
Unmethylated MethylatedMSI-H 25% 75%MSS 100% -
MLH
1 met
hylation
hMLH1 promoter hypermethylation is the main mechanism underlying MSI in SGC
Mismatch Repair (MMR) gene mutations are rare in sporadic gastric carcinomas
(Do not explain most of the MSI cases)
![Page 19: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/19.jpg)
MSI status
K-RAS Exon 1
BRAF Exon 15
MSI-H 10/36 (28%) 0/38 (0%)
MSS 0/46 (0%) 1/139 (0.72%)
p=0.0001 NP
KRAS and BRAF in sporadic gastric carcinoma
Oliveira et al, Oncogene 22: 9192, 2003Brennetot C et al, Gastroenterology 125, 2003
V600E
![Page 20: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/20.jpg)
S-Le x
Orcein staining
Venous invasion High expression of S-Lex
Absent 5.6%Present 94.4%
p=0.0025
Amado et al. Gastroenterology 114: 462, 1998
High S-Lex expression is a marker of poor prognosisin sporadic gastric cancer
![Page 21: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/21.jpg)
Histotype cases (n) CD44v6 overexpression (%)
Intestinal 14 7 (50.0)
Diffuse 13 10 (76.9)
Mixed 16 10 (62.5)
TOTAL 43 27 (62.8)
CD44v6 in sporadic gastric carcinoma
![Page 22: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/22.jpg)
Normal mucosa
IM (complete)
Dysplasia (low grade)
Hyperplastic polyp
IM (incomplete)
Dysplasia (high grade)
CD44v6 in precursor lesions of gastric carcinoma
![Page 23: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/23.jpg)
What about diffuse carcinoma?
CIN & Aneuploidy# 3p, 7q, 13q (LOH)# 6q (LOH)# 1q, 5q, 17p (LOH)RAS (overexpression/mutation)ERBB-2 (amplification)TPR-MET (rearrangement)c-MET (6.0 Kb mARN)EGF (overexpression)TGF-a (overexpression)
p 53 (LOH, mutation)APC (LOH, mutation)DCC (LOH)p 16 (hypermethylation)
MSI
S-Tn, T, S-TCDw75, S-Lex
Laminin, collagen IVu-PA, Cat-D NM 23 (loss)CD 44 (variants)
Diploidy# 3p, 7q, 13q (LOH)# 6q (LOH)
c-MET (6.0 Kb mRNA)
p 53 (LOH, mutation)
TGF-ß (overexpression)
K-SAM (amplification)E-cadherin (loss/mutation)
S-Tn, T, S-TCDw75, S-Lex
NM 23 (loss)CD 44 (variants)
E-cadherin gene (CDH1) plays the major role
Intestinal (glandular) carcinoma Diffuse (isolated cell) carcinoma
![Page 24: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/24.jpg)
E-Cadherin changes in diffuse carcinoma
CDH1 mutations(50% - 70%)
Somatic mutations
![Page 25: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/25.jpg)
E-cadherin gene alterations in sporadic gastric carcinoma
Machado JC et al. Oncogene 20:1525, 2001
MutationLOH
Promoter methylation
“2nd HIT”“1st HIT”
met unmet
![Page 26: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/26.jpg)
Inactivation of CDH1 in sporadic gastric carcinoma
![Page 27: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/27.jpg)
METHYLATION
NO ALTERATION
LOH+MUTATIONS
Inactivation of CDH1 in sporadic gastric carcinoma
![Page 28: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/28.jpg)
What about the mixed type of gastric carcinoma?
![Page 29: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/29.jpg)
Mixed gastric carcinomas show similar chromosomal aberrations in both their diffuse and glandular components
Diffuse component
Intestinal component
Carvalho B et al. Cellular Oncology 28:283, 2006
![Page 30: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/30.jpg)
What about the mixed type of gastric carcinoma?
E‐cadherin
![Page 31: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/31.jpg)
E-cadherin mutations in mixed gastric carcinomas
”Intestinal” component 17%”Diffuse” component 83%
Machado JC et al: E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas
Lab Invest 79: 459, 1999
![Page 32: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/32.jpg)
Histological type
Glandular (n=89)Isolated cell (n=14)Solid (n=28)Mixed (n=82)
5-year survival rate
52%67%48%16%
Carneiro F et al. Pathol Res Pract 191: 571, 1995
![Page 33: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/33.jpg)
Morphology Molecular pathology
![Page 34: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/34.jpg)
4-1-02 - ICD-O Code
Adenocarcinoma 8140/3 Papillary adenocarcinoma 8260/3 Tubular adenocarcinoma 8211/3 Mucinous adenocarcinoma 8480/3 Signet-ring cell carcinoma 8490/3
WHO – 3rd Edition
Signet ring cell ca? Mixed ca?
Some shortcomings:
![Page 35: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/35.jpg)
4-1 Gastric carcinoma Gregory Y. Lauwers Fátima Carneiro David Y. Graham Maria-Paula Curado Silvia Franceschi Elizabeth Montgomery Masae Tatematsu Takenori Hattori
4-1-02 - ICD-O Code Adenocarcinoma 8140/3 Papillary adenocarcinoma 8260/3 Tubular adenocarcinoma 8211/3 Mucinous adenocarcinoma 8480/3 Poorly cohesive carcinomas (including signet ring cell 8490/3 carcinoma and other variants)Mixed carcinoma 8255/3
WHO – 4th Edition, 2010
![Page 36: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/36.jpg)
Major histological
types
• pTNM• Venous invasion
• Sialyl-Lex
• ERBB-2• E-cadherin
• Microsatellite instability
Poor prognosis
Good prognosis
![Page 37: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/37.jpg)
Normal mucosa: neg
Intestinal metaplasia & dysplasia: pos
Sporadic gastric carcinoma
MSIIntestinal GC, older age
MLH1 methylation
Good prognostic biomarker
Oncogenic Mutations
KRAS negative
BRAF negative
EGFR positive
Biomarker for targeted therapy (EGFR inhibitors?)
CD44v6
New diagnostic biomarker
E-cadherin
Poor prognostic biomarkerLOH+ Mut
Nodal metastization, Advanced stage
![Page 38: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/38.jpg)
Sporadic cancer
Hereditary cancer(1-3%)
Morphology
Molecular pathology
![Page 39: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/39.jpg)
Gastric cancer in hereditary cancer syndromes
Syndromes Genetic alterations
• Lynch syndrome (HNPCC) MMR• Li-Fraumeni syndrome TP53• Peutz-Jeghers syndrome STK1• Familial adenomatous polyposis APC
![Page 40: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/40.jpg)
Sporadic (90%)
Familial Aggregation (10%)Familial Gastric Cancer (FGC)Familial Intestinal Gastric Cancer (FIGC)Familial Diffuse Gastric Cancer (FDGC)
Hereditary (1%)Hereditary Diffuse Gastric Cancer (HDGC)
GASTRIC CARCINOMA
![Page 41: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/41.jpg)
Maori kindred
Guilford P et al. Nature 392:402,1998
E-cadherin gene(CDH1) germline
mutations
Hereditary DiffuseGastric Cancer
![Page 42: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/42.jpg)
1999
E-cadherin changes in familial gastric cancer
2001
2003
Familial gastric cancer: overview and guidelines for management.
Prophylactic gastrectomies in asymptomatic carriers of germ-line E-cadherin mutations
Functional analyses of E-cadherin (CDH1)germline missense mutations
Model of development of HDGC2004
Cleft lip/palate and CDH1 mutations in families with HDGC
2006
2005 Report of the first Portuguese family with HDGC J Med Genet 36: 873, 1999
N Engl J Med 344:1904, 2001 Gastroenterol Clin Biol 25: 931, 2001 Hum Mutat 19:510, 2002 Hum Mol Genet 12: 575, 2003Hum Mol Genet 12: 3007, 2003 Oncogene 22:5716, 2003 J Pathol 203: 681, 2004Virchows Arch 446: 18, 2005 Clin Cancer Res 11:5401, 2005J Med Genet 43:138, 2006J Mol Med 84:1023, 2006 Hum Mol Genet15:1704, 2006 Hum Mutat 28:203, 2007Oncogene 27: 4255, 2008 J Clin Pathol 61:25, 2008 J Pathol 216:295, 2008 Gastroenterology 136:2137, 2009J Med Genet 47: 436, 2010
2007Novel germline CDH1 mutations
Experimental model in Drosophila
2008NMD mRNA surveillance downregulates aberrantCDH1 transcripts
Second hit of CDH1 inactivation
2009
2010
![Page 43: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/43.jpg)
CLINICALHISTORY
HISTOLOGICALCLASSIFICATION
MOLECULAR CLASSIFICATION
IDENTIFICATION OF FAMILIAL CASES
The story of hereditary diffuse gastric carcinoma
![Page 44: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/44.jpg)
HEREDITARY – Germline mutations
SPORADIC – Somatic mutations
E-cadherin mutations in diffuse gastric cancer
![Page 45: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/45.jpg)
HEREDITARY – Germline mutations
Missense mutations (20%)
Functional Assays in CHO cells (aggregation & collagen
invasion assays)
![Page 46: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/46.jpg)
Missense mutations affect cell-cell adhesion, motility and invasion
T340A, A634V, W409R,V832M, E757K
A617T, ….
Functional Irrelevant
“so-called variants”
Functional Relevant
Adhesion, Motility, Invasion
Suriano G et al. Hum Mol Genet 12:3007, 2003
![Page 47: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/47.jpg)
Oliveira C, 2010
![Page 48: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/48.jpg)
Oliveira C, 2010
![Page 49: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/49.jpg)
Oliveira C, 2010
![Page 50: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/50.jpg)
Familial gastric cancer: overview and guidelines for management
(International Gastric Cancer Linkage Consortium)
Carriers of germline E-cadherin truncating mutations
Caldas C, Carneiro F, Lynch H et alEur J Genet 36: 873, 1999
Intensive screeningProphylactic gastrectomy
![Page 51: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/51.jpg)
Carneiro F et al: J Pathol 203:68, 2004
In 9 prophylactic gastrectomies from North America
(Huntsman et al, 2001 and Chun et al, 2001),
all exhibited foci of intramucosal diffuse carcinoma
Hereditary diffuse gastric cancer (HDGC)
![Page 52: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/52.jpg)
E-cadherin germline mutations in HDGC
G62V
T118RP172R L214P
G239R
D244GA298T
T340A
W409RI415L
P429S
V487A
A592T
T599S
A617T
A634V R732Q P799R
V832M
TRUNCATING
MISSENSE
![Page 53: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/53.jpg)
In vivo validation of CDH1 germline missense mutations
Suriano G et alJ Mol Med 84:1023, 2006
![Page 54: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/54.jpg)
In vivo validation of in vitro assays of CDH1 missense mutations
Barber M et al J Pathol 216:295, 2008
![Page 55: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/55.jpg)
Barber M et al J Pathol 216:295, 2008
The highest number of foci was found in the fundus (44.7%) followed by the body (40.2%).
![Page 56: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/56.jpg)
Rogers W et alAm J Surg Pathol 32:799, 2008
70% of the total signet ring cell foci were locted within the proximal 1/3 of the stomach
![Page 57: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/57.jpg)
Gastrectomies in New Zealand in CDH1 carriers
Charlton A et al: Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut 53;814-820, 2004
![Page 58: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/58.jpg)
Total gastrectomies in asymptomatic CDH1 mutation carriers (n=96)(prophylactic gastrectomies & gastrectomies for early carcinoma)
• Intramucosal SRC carcinoma 87 (91%)
• Total gastrectomies studied under research protocol 73• Number of cases with intramucosal SRC carcinoma 70* (96%)
* 2/3 cases negative for SRC intramucosal carcinoma displayed in situ carcinoma
![Page 59: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/59.jpg)
Intramucosal signet ring cell (diffuse) carcinoma
![Page 60: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/60.jpg)
In situ (signet ring cell) carcinoma
Pagetoid spread of signet ring cells:
Two-layer structure: an inner layer composed of benign mucous cells
and an outer layer of signet ring cells.
![Page 61: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/61.jpg)
Pagetoid spread of signet ring cells and early invasion of lamina propria
![Page 62: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/62.jpg)
In situ (signet ring cell) carcinoma Pagetoid spread of signet ring cells:Two-layer structure: an inner layer composed of benign
mucous cells and an outer layer of signet ring cells.
Mucosa
Muscularis mucosa
Submucosa
T1aTisTNM stage
A B
Carneiro F, Charlton A, Huntsman D4th Edition of WHO book , 2010
![Page 63: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/63.jpg)
Non-neoplastic mucosawith foveolar hyperplasia
In situ signet ring cellcarcinoma
In situ signet ring cellcarcinoma and pagetoid spread
CDH1 germline mutation
Inactivation of second allele of CDH1
?
Pagetoid spread of signetring cell carcinoma
Early invasive (intramucosal)signet ring cell carcinoma
C D EA B
Development model of HDGC
Carneiro F et alJ Clin Pathol 61:25, 2008
![Page 64: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/64.jpg)
CLINICALHISTORY
HISTOLOGICALCLASSIFICATION
MOLECULAR CLASSIFICATION
First Portuguese HDGC Family (Porto)
Second Portuguese HDGC Family (Coimbra)
![Page 65: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/65.jpg)
Genetics, Pathology and Clinics of Familial Gastric Cancer
The story of Hereditary Diffuse Gastric Cancer (HDGC)
![Page 66: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/66.jpg)
Methylation
DNA demethylating agents
Gene structure alterations
Partners of E-cadherin signalling
2nd HIT of CDH1 silencing?
ModulatorsE-cadherin expression
![Page 67: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/67.jpg)
Carla Oliveira Gianpaolo SurianoJosé Carlos MachadoCéu FigueiredoPaulo FerreiraRita MateusRachid KaramHerculano MoreiraManuel Cardoso de OliveiraFátima CarneiroRaquel SerucaManuel Sobrinho-Simões
Paul PharoahCarlos Caldas
Department of Oncology, University of Cambridge UK
David HuntsmanDavid Owen
Thomas Smyrk
J. van KriekenJ de Bruin
Hospitais da Universidade de Coimbra
Augusta CiprianoMário Rui Silva
VU University Medical CenterBeatriz CarvalhoGerrit Meijer
Academic Medical CenterJohan OfferhausAnya Milne
![Page 68: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/68.jpg)
THANKS FOR YOUR ATTENTION
![Page 69: Molecular Pathology of Gastric Canceracmcb.es/files/425-1495-DOCUMENT/Carneiro-3-17Feb11.pdf · Molecular Pathology of Gastric Cancer Fátima Carneiro IPATIMUP & FMUP/HSJ Porto, Portugal](https://reader031.vdocuments.net/reader031/viewer/2022013020/5eadc43e8a2d8244b023ec59/html5/thumbnails/69.jpg)
First Portuguese Family with HDGC (Porto)
Second Portuguese Family with HDGC (Coimbra)
Oliveira et al: Virchows Arch 446: 181-184, 2005