Colon Cancer and Hereditary Cancer Syndromes
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1 Colon Cancer and Hereditary Cancer Syndromes Gisela Keller Institute of Pathology Technische Universität München
2 Colon Cancer and Hereditary Cancer Syndromes epidemiology models of colorectal carcinogenesis tumor suppressor genes and oncogenes molecular classification
3 World: Estimated incidence and mortality, both sexes Globocan 2012, IACR: International Agency for Research on Cancer
4 Colorectal Cancer in Germany new cases /year 2010 Second (women) and third (men) most common cancer Robert-Koch Institut 2013
5
6 Genetic Model of Colon Carcinogenesis (Fearon-Vogelstein Model) alterations in 4 to 6 genes alterations in a preferential sequence accumulation is important activation of oncogenes and inactivation of tumor suppressor genes
7 Colorectal Cancer and Age from: Varmus und Weinberg, Gene und Krebs, Spektrum der Wissenschaft 1992
8 Colorectal Cancer and the Number of Alterations as Rate Limiting Events one event 2 events 4-6 events from: Varmus und Weinberg, Gene und Krebs, Spektrum der Wissenschaft 1992
9 Adenomas benign epithelial neoplasia exophytic growth pattern atypic nuclei (enlarged, hyperchromatic spindleshaped, ovoid) normal epithelia tubular adenoma
10 adenoma carcinoma modified from
11 Adenoma Carcinoma
12 Accumulation of Genetic Alterations in the Adenoma-Carcinoma-Sequence Fearon ER and Vogelstein B: A Genetic Model for Colorectal Tumorigenesis. Cell 61: , 1990
13 Genetic Alteration in the Adenoma-Carcinoma-Sequence normal epithelia hyperproliferative epithelia adenoma carcinoma APC LOH 5q
14 APC Gene (adenomatous polyposis coli) chromosome 5q21 multiple functions - cell adhesion, migration - chromosome segregation, genetic stability - Wnt-signaling
15 Colon Epithelium APC and Wnt-Signaling Reya and Clevers (2005), Nature 434: Elisabeth Pennisi (1998), Science 281:
16 APC Gene (adenomatous polyposis coli) chromosome 5q21 multiple functions - cell adhesion, migration - chromosome segregation, genetic stability - Wnt-signaling tumor suppressor gene - somatic mutations: 40-70% of adenomas and carcinomas - germline mutations: FAP-syndrome (familial adenomatous polyposis coli)
17 Tumor Suppressor Genes suppress cell proliferation multiple functions signal transduction cell cycle regulation apoptosis DNA-repair loss of function important
18 Two Hit Model of Inactivation of Tumor Suppressor Genes (Knudson 1971) 1. mutation germline 1. mutation somatic 2. mutation somatic 2. mutation somatic colon of a 30 year old FAP patient sporadic tumor hereditary tumor
19 Familiar Adenomatous Polyposis Coli (FAP) germline mutations in the APC gene autosomal dominant inherited tumor disease > 100 adenomas in the colon high cancer risk early age on onset frequency: 1% of colorectal carcinomas
20 Genetic Alterations in the Adenoma-Carcinoma-Sequence normale epithelia hyperproliferative epithelia adenoma carcinoma APC LOH 5q K-ras
21 Oncogene activated protooncogene promote cell proliferation
22 K-ras (Kirsten rat sarcoma viral oncogene homolog) somatic mutations - in 40-50% of carcinomas and adenomas (> 1cm) G-protein signal transduction (receptor tyrosine kinase, e.g. EGFR = epidermal growth factor receptor)
23 Function and Activation of K-ras Signal transduction Oncoprotein Gschwind et al. 5 : , 2004.
24 Oncogenes in Colorectal Tumors K-ras mutations in 40-50% of carcinomas and adenomas ( >1cm) G-protein signal transduction c-myc overexpressed in up to 70% of carcinomas transcription factor EGFR overexpressed in 30-80% of carcinomas receptor for the growth factor EGF
25 Receptor Tyrosine Kinases as Therapeutic Targets Antibodies against EGFR: Cetuximab Treatment of metastatic colon carcinomas Gschwind et al. 5 : , 2004.
26 K-ras Mutation and Therapy Response 89 patients with metast. CRC therapy with Cetuximab mutated K-ras nonmutated progression free survival mutated K-ras nonmutated overall survival Gschwind et al. Nature Rev Cancer 5 : , Lievre, A. et al. JCO, 26:
27
28 Randomized study (n=394) Cetuximab + best supportive care versus best supportive care alone Median OS: 9.5 versus 4.8 Monate Result K-ras mutations: 42.3%
29 ...The European regulatory agency has already changed the cetuximab label, restricting ist use to patients with wild-type K- Ras... Journal of the National Cancer Institute Advance Access originally published online on November 25, 2008 NEWS K-Ras Mutations Are Changing Practice in Advanced Colorectal Cancer Caroline McNeil Last month, an expert panel said that patients with advanced colorectal cancer should not be treated with cetuximab or panitumumab if their tumors have mutations in the K-Ras oncogene. This is really a sea change in practice
30 Mutationsanalytik TUM-Pathologie KRAS Analysen Jahr
31 Genetic Alterations in the Adenoma-Carcinoma-Sequence normale epithelia hyperproliferative epithelia adenoma carcinoma APC LOH 5q K-ras DCC SMAD 2/4 LOH 18q
32 DCC (deleted in colorectal cancer) SMAD2/4 (mother against decapentaplegic homolog) tumor suppressor gene, chromosome 18q21 LOH 18q: 50% of late ademonas 70% of carcinomas DCC mutations: 6% of carcinomas reduced expression: 30% of carcinomas cell adhesion, migration SMAD2/4 mutations:14% of carcinomas TGF-b signaling
33 Genetic Alterations in the Adenoma-Carcinoma-Sequence normal epithelia hyperproliferative epithelia adenoma carcinoma APC LOH 5q K-ras SMAD2/4 LOH 18q TP53 LOH 17p
34 TP53 tumor suppressor, chromosome 17p13 somatic mutations: 50% of carcinomas LOH: 75% of carcinoma protein of 393 amino acids, MW 53kdal multiple functions cell cycle control (G1-S checkpoint ) DNA repair apoptosis
35 Genetic Model of Colon Carcinogenesis (Fearon-Vogelstein Model) alterations in 4 to 6 genes alterations in a preferential sequence accumulation is important activation of oncogenes and inactivation of tumor suppressor genes
36 Science Oct 11; [Epub ahead of print]
37 The Genomic Landscapes of Colon and Breast Cancer: Mutations sequencing of genes in 11 tumors number of mutations / tumor - colon: 77 - breast: 101 Identification of 280 CAN (cancer)-genes Number of mutated CAN-genes / tumor - colon: 15 - mamma: 14 only few CAN-genes are commonly mutated large number of genes are mutated at low frequency large tumor heterogeneity
38 APC TP53 K-ras Fig. 3 Cancer genome landscapes Few gene mountains, many gene hills Wood LD et al., Science 2007, Oct 11
39 Genetic Alterations in the Adenoma-Carcinoma-Sequence normal epithelia hyperproliferative epithelia adenoma carcinoma APC LOH 5q K-ras SMAD2/4 LOH 18q TP53 LOH 17p chromosomal instability
40 Molecular Classification of Colorectal Carcinomas chromosomale instability (CIN)
41 Molecular Classification of Colorectal Carcinomas chromosomale instability (CIN) microsatellite instability (MSI)
42 Microsatellites short repetitive DNA-sequences CA CAGTAA widely distributed in the genome function unknown highly polymorphic
43 replication replication Mismatchrepair proteins MSH2 / MSH6 MLH1 / PMS2 replication insertion Microsatellite instability deletion
44 Microsatellite Instability BAT 25 Normal Tumor BAT 26 Normal Tumor
45 Molecular Classification of Colorectal Carcinomas chromosomal instability (CIN) microsatellite instability (MSI) -MSI-H: > 2/5 markers unstable -MSI-L: 1/5 marker unstable -MSS: stable
46 Microsatellite Instability (MSI) and DNA - Mismatch Repair Genes MSI - additional alleles in the tumor defects in mismatch repair genes MLH1, MSH2, MSH6, PMS2 mutations in genes with repetitive sequences in the coding region TGF-b-receptor type II, IGFII-receptor, axin2, bax MSI-H in colorectal carcinomas - sporadic: 15-20% - hereditary (HNPCC): 80-90%
47 Lynch-Syndrome (HNPCC - hereditary nonpolyposis colorectal cancer) germline mutations in DNA-mismatch repair genes (MLH1, MSH2, MSH6, PMS2) tumor spectrum colon extracolonic (endometrium, stomach, small intestine, urothel carcinomas) syn-, metachrone carcinomas early age of onset frequency: 2-3% of colorectal carcinomas
48 Immunohistochemistry: MMR - Proteins MSH2 MSH6 MLH1 PMS2 Germline mutation: MLH1, c.511g>t, p. Glu171Stop
49 Pedigree of an HNPCC-Family Colon-Ca ED: 32J Colon-Ca, Endometrium-Ca ED: 35J Colon-Ca, DD-Ca ED: 30J
50 Molecular Classification of Colorectal Carcinomas chromosomal instability (CIN) microsatellite instability (MSI) -MSI-H: > 2/5 markers unstable -MSI-L: 1/5 marker unstable -MSS: stable epigenetic instability CpG island methylator phenotype (CIMP) -CIMP-H: >30% methylated genes -CIMP-L: <30% methylated genes
51 Epigenetic Alteration: DNA-Methylation covalent modification of cytosine (CpG sites) function: - gene expression - chromosomal stability 70% of CpGs are methylated CpG islands in promoter regions are not methylated, transcription possible promoter hypermethylation silencing of transcription
52 Colorectal Carcinogenesis classical adenoma-carcinoma-sequence serrated carcinogenesis
53 Serrated Morphology of Epithelial Crypts
54 Serrated Carcinogenesis activation of the MAPK-signaling -BRAF -KRAS inhibition of apopotosis serrated morphology DNA methylation CpG island methylator phenotype (CIMP) -CIMP-H: >30% -CIMP-L: <30% methylated genes
55 Sessile serrated carcinogenesis normal epithelia HP? BRAF sessile serrated adenoma CIMP-H methyl. MLH1 mut. TGbRII, IGFR2 partial methyl. MLH1, methyl. MGMT mut. p53 carcinoma MSI-H carcinoma MSI-L, MSS
56 Sessile serrated carcinogenesis normal epithelia HP? BRAF sessile serrated adenoma CIMP-H methyl. MLH1 mut. TGbRII, IGFR2 partial methyl. MLH1, methyl. MGMT mut. p53 carcinoma MSI-H carcinoma MSI-L, MSS Traditional serrated carcinogeneis mixed type normal epithelia HP? KRAS traditional serrated adenoma (TSA) / villous adenoma CIMP-L methyl. MGMT CIN mut. p53, APC LOH 3p, 18q carcinoma MSI-L, MSS
57 Clinical Characteristics Sessile serrated carcinogenesis sessile serrated adenoma carcinoma MSI-H carcinoma MSI-L, MSS proximal localization sex: F>M low-risk-subtype 5 year survival >70% high-risk-subtype Traditional serrated carcinogenesis 5 year survival <30% traditional serrated adenoma/ villous adenoma carcinoma MSI-L, MSS distale localization sex: M>F
58 Molecular Classification of Colorectal Carcinomas serrated pathway CIMP- H CIMP-L K-ras, p53- mutation MLH1-methyl. BRAF-mutation MSI-H 8% 20% 12% 3% CIN 57% classical adenoma carcinoma pathway APC, K-ras, p53 mutation CIMP-negativ from: Jass JR, Histopathol 2007, 50:
59 Nature Jul 18;487(7407): Comprehensive molecular characterization of human colon and rectal cancer. Cancer Genome Atlas Network. Collaborators (326) Genomweite Analysen von 276 Karzinomen Exom-Sequenzierung DNA-Kopien-Anzahl Promoter-Methylierung mrna-expression microrna-expression
60 Mutation frequencies in human CRC. The Cancer Genome Atlas Network Nature 487, (2012) doi: /nature11252
61 Diversity and frequency of genetic changes leading to deregulation of signalling pathways in CRC. The Cancer Genome Atlas Network Nature 487, (2012) doi: /nature11252
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