Of Colorectal Cancer CRC Dr Calypso Barbatis MD FRCPath PhD HBD Histobiodiagnosis ATHENS HSGO 1920 May 2018 ATHENS Frequent malignancy 3 rd cause of cancerrelated mortality ID: 1047599
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1. Molecular Pathological ClassificationOf Colorectal Cancer (CRC)Dr. Calypso BarbatisMD, FRCPath, PhDHBD Histobiodiagnosis ATHENSHSGO / 19-20 May 2018ATHENS
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3. Frequent malignancy3rd cause of cancer-related mortalityworldwideSporadic, Hereditary, FamilialRelated to IBDPrecursor LesionsAlmost perfect stepwise model of carcinogenesisConventional adenoma Serrated lesions CRC
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5. Specific features of CRCHeterogeneous Disease in morphologysitegenderageresponse to treatmentSource: Pol J Path. 2014; 65(4): 257-266. Bosman FT, Yan P.
6. Does CRC fit to the P4 medicinePredictivePersonalisedPreventiveParticipatorySource: Hood L, Friend SH. Nat Rev Clin Oncol 2011;8: 184-187
7. Classical evidence-basedClinicopathological parameters Still determine treatmentButThe road to molecular classification has opened and awaits full implementation whenclinical translation and precision medicine are approved
8. The classification of CRCis based on clinicalmorphologicalmolecular featuresand available markersprognosticpreventive
9. Current non-molecular classificationof CRCSiteSubsite (the most involved)Rectal: Inferior margin <16 cm from the anal vergeorif any part of the tumor is located within the supply of the superior rectal artery
10. WHO Histological typesConventional adenocarcinomaMucinous (colloid) adenocarcinoma ( > 50% mucin)Signet-ring cell carcinoma ( > 50% signet-ring cells)Medullary carcinomaMicropapillarySerratedSquamous cell carcinomaAdenosquamousSpindle cellPoorly differentiated neuroendocrine carcinomaLarge cell neuroendocrine carcinomaSmall cell neuroendocrine carcinomaMixed adenoneuroendocrinUndifferentiated
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12. Histological GradeGrade 1,2,3,4 (Undifferentiated)TNM Stage (T0, T1,T2, T3, T4)Nx, N0, N1, N2M: M0, M1a, b, c (metastasis to the peritoneum with or without other organ involvementTumor buddingPerineural/Lympho-vascular invasionPerforationAssesment of mesorectal envelopeMarginsTreatment effect (Tumor regression score)0 Complete response1 Near complete response2 Partial response3 Poor non responseSource: Amin MB et al eds. AJCC Staging manual 8th edition 2017
13. Basic pathways in colorectal cancerEast et al, British Society of Gastroenterology position statement on serrated polyps in the colon and rectum.GUT 2017
14. Pathogenesis of colorectal cancer GENETIC AND EPIGENETIC CHANGESA.GENETIC EVENTS1.CHROMOSOMAL INSTABILITY (65-70% of sporadic CRC)a)AneuploidyChromosomal gainsChromosomal lossesb)LOH=loss of the entire gene and the surrounding chromosomal region.CAUSES:Chromosomal segregation defects,DNA damage repair,telomere dysfunction, point mutations of oncogene or tumor suppressor genes.Mutational status:APC,K-RAS,SMAD2-SMAD4,p53Mc Granahan et al,2012 EMBO ReportsFredericks et al, J Cancer Biol Res 3(1): 1057
15. GENETIC AND EPIGENETIC CHANGESB.EPIGENETIC EVENTSEpigenetic changes are those inheritable changes in gene expression with no alterations in DNA sequences.DNA methylationHistone modificationMicro-RNAs (non coding RNAs)Chen et al,Oncology reports,2013
16. Molecular pathways of CRC carcinogenesis1. Classical carcinogenetic modelChromosomal instability (CIN)Marked aneuploidy1st pathogenetic eventAPC gene mutationsAllelic lossSomatic gene amplificationTranslocationActivationWNT signaling pathway
17. Apc/B-CATENIN PATHWAY CIN MECHANISMS=APC MUTATIONS Wnt/pathway activationB-catenin in cytoplasm and in nucleusTrascription factors promote proliferationAccumulation of mutations/EGFR activation Kras mutationsLoss of SMAD2 SMAD4Loss of p53EMT mechanisms activationSlaby et al,Molecular Cancer2009
18. 2nd Pathway (MMR gene system or MSI)Inactivation of MMR genesInactivation of suppressor genesLynch syndrome(Diploid tumors with MSI)
19. The Serrated pathway Hypermethylation of specific DNA regionsnearthe “promoter genes” the CpG islandsDiploid tumorsSilence of Tumor Suppressor Genes
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21. Msi pathway (1)MICROSATELLITE INSTABILITY (15% of colorectal cancer)Inactivating mutations in the DNA mismatch repair genes (MMR) or methylation of the gene promoter that codify for ATPases such as hMLH1,hMSH2 hPMS2, MSH6,MSH3.Imai et al,Carcinogenesis vol.29 no.4 pp.673–680, 200810-15% of sporadic colorectal carcinoma CIMP-H frequent BRAF mutated.Lynch syndrome 3-5% of all colorectal carcinomas.No BRAF mutations.
22. The cimp pathwayCIMP stands for CpG island methylator phenotype.1. Transcriptional inactivation of genes that have tumor suppressive roles or they are involved in cell cycle.2.BRAF mutation is an early genetic event in this pathway3.MLH1 hypermethylation is commonly seen.4.Other promoters also hypermethylated are:CDKN2A,MGMT tumor suppressor genes,MUYTH polyposis syndrome-BER genes,TIMP3 ecc.5.CIMP-H,CIMP-L,CIMP-normal classification.Tariq et al, Cancer Biol Med 2016Schaafsma et al, Biol Med 2016
23. Classification by molecular subtypesThe Cancer Genome Atlas (TCGA)Consensus Molecular Subtypes (CMS)Sources: Nature. 2012; 487: 330-7 (TCGA)Comprehensive molecular characterizationof human colon and rectal cancerNat Med. 2015; 21: 1350-6The consensus molecular subtypesof colorectal cancer. Guinney J et al.
24. Purpose of classification“To correlate cancer cell phenotypewithclinical behavior and provide guidance to rational treatmentwith specific targeted therapies”(CRC subtyping Concortium)This was attempted by the knowledge of gene expression databased on“epigenomic, transcriptomic, microenviromental, genetic and clinical characteristics of tumors’’
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27. Consensus Molecular Subtypes of colorectal cancer (CMS)Assessment methodsMutationsChromosomal number alterationsMethylation statusPosttranslationalGene regulationClinical analysis (site, gender, grade, stage)DFS (Disease Free Survival)RFS (Relapse Free Survival)SAR (Survival After Relapse)IMPORTANT!!“No subtype was solely defined by a genetic aberration”wild-type KRAS may be found in all subtypes
28. Clinical implications of CMS CMS1 (MSI) Better prognosis before disseminationWorst prognosis after relapseStages 1,2 perhaps no adjuvant chemotherapyStage 3 no response to 5-FUImportance of the immunogenic microenvironmentTreatment? Check point inhibitors
29. CONSENSUS MOLECULAR GROUP 1https://familyhistorybowelcancer.wordpress.com/hereditary-colorectal-cancer-syndromes
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31. CMS2 Canonical (adenoma – CRC sequence)APC lossKRAS activationP53 lossCIN increased copies of oncogenesreduced copies of suppressor geneslow mutation rate ( < 8 mutations / 106 bases)adjuvant chemotherapy
32. Consensus MOLECULAR GROUP 2http://www.imagingpathways.health.wa.gov.au/index.php/imaging-pathways/gastrointestinal/gastrointestinal/staging-of-colorectal-cancer
33. CMS3 metabolic subtype30% hypermutatedKRAS mutationTubulovillous adenoma with serrationPrecursor lesion (?)Enriched in RNA (9-10 metabolic pathways)Glutamine, fatty acid, phospholipid metabolismPoor prognosis of KRAS mutated casesHer-2 mutations Resistance to EGFR mAb
34. CONSENSUS MOLECULAR GROUP 3http://www.thepinsta.com/adenocarcinoma_8zBRakAGoyf3SGdDDmkNXug7gO9Fo6YlJVf7hsFfvWU/
35. CMS4 (mesenchymal)Advanced stage in diagnosisPoor survival (62% in 5 years)Resistant to anti-EGFRRegardless of KRAS mutation statusDifficult to treat? use of microenvironment features? anti avβ6 integrin Anti-CAFAnti-macrophageSource: Thanki K et al. IBBJ 2017; 3(3) 105-111
36. CONSENSUS MOLECULAR GROUP 4DAWSON et al Reviews in medicine 2015
37. Molecular features of CRCMolecular HeterogeneityGenomic, epigenomicdefine Molecular subtypesImplementation ofPersonalized therapiesImprovement of management
38. AcknowledgementMy gratitude to Dr.Bouklas for providing some of the tables and additional literature
39. Thank You For Your Attention