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InSiGHT’s history

International Society for Gastrointestinal Hereditary Tumours (InSiGHT): Edited highlights D ü sseldorf, 2009. InSiGHT’s history.

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InSiGHT’s history

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  1. International Society for Gastrointestinal Hereditary Tumours (InSiGHT): Edited highlightsDüsseldorf, 2009

  2. InSiGHT’s history • In 1985 polyposis experts (Dukes, Bussey, Morton et al … ) met at Leeds Castle, Kent, UK. In 1989 the Leeds Castle Polyposis Group (LCPG) was formally established. • The International Collaborative Group on Hereditary Non Polyposis Colorectal Cancer (ICG-HNPCC) was conceived in Jerusalem, in 1989. • In 1990 the first formal meeting of the ICG-HNPCC was organized in Amsterdam. • In 1997 the first joint meeting of LCPG and ICG-HNPCC took place in Noordwijk. • At the meeting in Venice in 2001 it was agreed that the ICG-HNPCC should formally merge with the LCPG to form a new society. • InSiGHT’s journal is Familial Cancer • www.insight-group.org • Members include physicians, geneticists, surgeons, pathologists, scientists, counsellors etc • It co-ordinates Registries on an International basis

  3. Pre-meeting • UVs • Feedback from Sian Tavtigian post-Lyon Feb 09 • Adding phenotype to InSiGHT mutation database • Functional assays • Worldwide collaborative project on UVs • International interpretation panel • Feb 2013 InSiGHT meeting in Melbourne will be linked to HVP • Nature Genetics paper of all 10,000 MMR mutations

  4. Phenotype • No phenotype • FHx +/- • AC +/- • Summary FH based on Barnetson & Chao • Pedigree (for segregation)

  5. Algorithms • Family mutation probability: Wijnen • Individual mutation probability: Barnetson R et al NEJM 2006; 354:2751-63. • [See also thePREMM1,2,6 model] • Developed from a population <55y and validated on a population <45y. ?performance >55 • https://hnpccpredict.hgu.mrc.ac.uk • Pr/(1-Pr) = 1.39 x 0.89Age x 2.57Gender x 4.45Location x 9.53Sync/Met x 46.26CRCFH(<50) x 7.04CRCFH(=>50) x 59.36ECFH • Stage 1 and Stage 2 * Age is expressed in years at time of diagnosis * Gender is 1 = male, 0 = female * Location is 1 = proximal, 0 = distal tumours (Proximal colon = any of the following sites Splenic flexure, Transverse colon, Ascending colon/hepatic flexure, Caecum, Appendix) * Synchronous and/or metachronous tumours are: Sync/MetTumour = 1 and no Sync/MetTumour = 0; * There are three possible colorectal cancer family history categories CRCFH(<50) and CRCFH(>=50): 1 and 0 if the youngest affected first degree relative was aged <50yrs 0 and 1 if the youngest affected first degree relative was aged >=50yrs 0 and 0 if there were no affected first degree relatives; * Family history of endometrial cancer: ECFH = 1 if there are any first degree relatives with endometrial cancer ECFH = 0 if none.

  6. InSiGHT summary FH phenotype dataset • As these phenotype parameters are used to assess mutation probability, they can be used to inform the Bayesian probability of risk for any unclassified variant. Hence: • Stage 1 • Age, gender, location, sync/met, FH, ECFH • Stage 2 • IHC • MSI • Stage 3 • Additional family data: e.g. # affecteds • Co-segregation

  7. UVs likelihood ratios • Five classes • 5: >0.99 • 4: 0.95-0.99 • 3: 0.05-0.95 • 2: 0.001-0.05 • 1: <0.001 • Need to quantitate “natural variation” in results • HGVS @ UNESCO HQ, Paris, Jan [May] 2010

  8. Functional assays • (IHC) • Robert Hofstra, Leiden • Couch FJ Hum Mutation 29:1314-26 • Assymetrical F-tagged PCR construct with an engineered mismatch • In vitro expression of MSH2 etc • Add to –MSH2 brew • Relative heights of cut/uncut peaks gives measure of in vitro activity • Quick, cheap, simple, easy …

  9. PMS2 & BRAF status • Abnormal PMS2 expression alone in tumours • Strong indicator of PMS2 mutations • MLH1 + PMS2 absent … but weak MLH1 on re-testing ! • iQC & EQA • Others find (uninterpretable) complex combinations of IHC abnormality • Tumours with BRAF V600E in PMS2 families • Probably sporadic • Due to ascertainment bias consequent upon clinical referral criteria • PMS2 carriers ascertained secondary to homoz children have v little if any FH

  10. Genome-Wide Association Studies • Houlston, Dunlop, Tomlinson, Gallinger, Peters et al • 10 SNPs = 6% of FCRC risk • Nature Genetics 40:1426-35 • [100 SNPs = 80%] • [172 SNPs = 100%] • Issues: • Population heterogeneity • Rare private variants • Incomplete SNP capture • Copy Number Variants need studying • Gene-Environment and GxG interactions • Deep re-sequencing needed, to find private variants % of FCRC risk SNPs (n)

  11. Genome-Wide Association Studies • LS Modifiers (Houlston) • CycD1 G242A MSH2, but not MLH1 • MTHFR • C677T & age of onset – iffy • A1298C – iffy • but compound hets 15 y younger • IGF1(dinuc) <18rpts = younger onset & age of onset α 1/rpt • RNASEL R462Q • HFE (?) • … 4 others

  12. Main meeting

  13. PMS2-PMS2CL hybrids, Wimmer • PMS2-PMS2CL hybrid alleles • Inv dup 7p22.1 • φ = exons 9, 11-15 • Non-homol recomb • Allele drop out • Hybrid 1-12,φ13-15 • PCR by exon specific SNPs - 13: 2253T/C; 14: 2324A/G; 15+ *92dupA • 98/300 alleles are hybrid

  14. MSI tumour immunology • Tumour infiltrating lymphocytes . in tumours with MSI • Novel antigens in MSI tumours due to coding microsatellite (MS) mutations

  15. MSI tumour immunology • T cell Immune responses • FrameShiftPolypeptide-specific T cells are present but tumours grow • FSP-specific T cells are present in LS patients, without tumours … • Patients are probably being immunised by tumours which never present clinically • Humoural IR • Highest after resection or adv tumours • Low level ab in healthy LS pts • Immune evasion: • HLA Class I expression is lost because of beta2M/HLA A2 – coding MS muts • Known for a long time • New finding: • HLA Class II is lost through CIITA 1962_1963insC , RFX5 56delC, RFXANK, RFXAP muts

  16. MLH1 epimutations, Megan Hitchins • MLH1 epimutation segregates in a 3 gen fam • Soma-wide, allele specific, mosaic • T allele methylated • Loss of T allele in mRNA • + loss of C allele in tumour • 3 affecteds and 5 unaffecteds had soma methylation (14-49%) • AD transmission • Father’s sperm demethylated • Son has soma methylation • So, now reversible non-Mendelian & Mendelian MLH1 epimutation • ?distinct mechanisms

  17. EPCAM/TACSTD1 EPCAM MSH2 • Different deletions, vary in size, cause same effect • Methylation of MSH2 promotor • Common Dutch founder EPCAM c.859-1462_*1999del • 5 patients • 1 AC+ • 4 FH • CRCa x31, DUCa x1, SBCa x2, BRCa x1, PRCa x3, Leuk x2, ENCa x0 • Homoz mutn of EPCAM causes congenital tufting enteropathy • ?hemizygosity contributes to cancer AluJo

  18. CAPP2, Burn • LS pts treated with • Aspirin 600 mg/d • Resistant starch 30 g/d • Both • Neither (placebo) • for • 29 months (7-74 months) • No apparent initial effect on tumour incidence, but delayed action, and significant effect now being seen (as in other aspirin studies) • Fodde: aspirin attenuation of betaCATenin/TCF4 pathway, ^stability of betaCAT • Ca stem cells produce IL4, but aspirin inhibits IL4

  19. Novel CRCa genes, Katachalam • 32 YOCC with MSS tumours • aCGH • Novel CNVs in 5 • Dup PTPRJ/DEP-1 11p11.2 • 110-160 Kb, contains 1-2 genes • Candidate human TSG & mouse susceptibility locus • So, 3 lines of evidence suggesting significance • 1500 Fam CRCa + controls tested for the CNV • 2 dups and 4 dels • Various sizes • ? Why both del and dup associated with same phenotype

  20. MMR mut prob model, Kastrinos • MMRpredict • MMRpro • PREMM1,2,6 • http://www.dfci.org/premm

  21. MSH6 risks, Jenkins • 70y 80y HR • CRCa M 22% 44% 7.6 • F 10% 20% • ENCa 26% 44% 26 • Others* M 3% 6% 0.8 • F 11% 22% 6 • *Gastric, Small bowel, Kidney, Ureter, Ovary, Brain • Differences between 70 and 80 are due to large rise in population risks at this age

  22. MSH2 extracolonic risks (Standardised Incidence Ratios), Engel (German Registry) • M F SIR • Bladder x75y 10.1 15.4 7.6 • 5.8% 4.8% • Breast 1.84 (1.4 – 2.4) • 15.1% • Ovary 13.4 MSH2/6 highest • 8.0% MLH1 lower • MLH1MSH2MSH6 • Gastric, SB High High Low • Bladder Low High Low • Ovary (low) High High

  23. HFE and CRCa risk, Scott • HFE C282Y and H63D • x3 CRCa risk • H63D HR 2.93 (1.3 – 6.4) p 0.007 • If H63D homoz then ~6y earlier onset • Shiu et al Int J Ca 125:78-83 • However: • HFE is within HLA on chr 6, so is this an association with HLA and not HFE per se … • Another group reported an association with C282Y but not H63D, so could well be either a ‘spoof’ association or very population specific, implying HLA not HFE.

  24. LS Modifiers, Wijnen • 14 SNPs associated with CRCa • Are they associated with LS risks? • On testing Leiden’s mega set of LS families: • All M F • 8q23.3 (x2) x3 rs16982766 C allele • (related to MYC) • 11q23.1 x3 rs3802842 • 4q13.1 x2 rs4355419 • >3 risk alleles increase risks further • ?warrants more intensive surveillance

  25. Prostate Ca risk in LS, Pål Møller • MSH2, MLH1, MSH6 • Obs 9 cases of PRCa, expected 1.52, p <0.01 • MSH2 MLH1 MSH6 PMS2 • 6 0 2 1 • 7/8 tumours abnormal IHC • Age 60.4, cf. 66.6, p <0.01 • 5/8 had high Gleason scores (8-10), v signif.

  26. IHC in LS, Klarskov & Frayling • Interobserver variability • Variability • Tyros and experts no different • UK NEQAS ICC • Technical scheme • ~50% of 55-74 labs score <12

  27. MutYH • Elke Holinski-Feder • MutYH mutations now observed in a wide variety of phenotypes: FAP, AFAP, ATFAP • Christina Thirlwell, London • E466X diagnosed 10y earlier than Caucasians with 165/382 • Later stage Ca • ?more adenomas • Café-au-lait spots ?! • Sampson • CRCa risk in carriers • SIR 2.12 (1.3-3.3)

  28. MutYH • Elke Holinski-Feder • MutYH mutations now observed in a wide variety of phenotypes: FAP, AFAP, ATFAP • Christina Thirlwell, London • E466X diagnosed 10y earlier than Caucasians with 165/382 • Later stage Ca, ?more adenomas, Café-au-lait spots ?! • Sampson • CRCa risk in carriers SIR 2.12 (1.3-3.3)

  29. Hereditary Pancreatic Ca, Bartsch • Testing • BRCA2 if 2 FDR with PACa, or any 3 rels with PACa • p16 if malignant melanoma in F/SDR of PACa case • PRSS1, MMR, LKB1, ATM, APC as per FH

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