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INTERNATIONAL SARCOMA KINDRED STUDY: FIRST GENE SCREENS

INTERNATIONAL SARCOMA KINDRED STUDY: FIRST GENE SCREENS. ISKS cohort. ISKS hereditary cancer syndromes. 658 ISKS families. 109 Uninformative. 104 No cancer in 1 o /2 o rels. 337 No defined syndrome. 108 Recognised syndrome. 268 Not suspicious. 69 Clinically suspicious. 42 +.

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INTERNATIONAL SARCOMA KINDRED STUDY: FIRST GENE SCREENS

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  1. INTERNATIONAL SARCOMA KINDRED STUDY:FIRST GENE SCREENS

  2. ISKS cohort

  3. ISKS hereditary cancer syndromes 658 ISKS families 109 Uninformative 104 No cancer in 1o/2orels 337 No defined syndrome 108 Recognised syndrome 268 Not suspicious 69 Clinically suspicious 42 + 16 ++ 11 +++ 56 Chomp/LFS 21 BRCA 17 Lynch like 14 Other

  4. ISKS hereditary cancer syndromes 658 ISKS families 109 Uninformative 104 No cancer in 1o/2orels 337 No defined syndrome 108 Recognised syndrome 268 Not suspicious 69 Clinically suspicious 42 + 16 ++ 11 +++ 56 Chomp/LFS 21 BRCA 17 Lynch like 14 Other 19% of these families were referred to a familial cancer clinic

  5. Cancer genes: frequency and penetrance Rare high penetrance Common low penetrance

  6. Cancer genes: frequency and penetrance Rare high penetrance Common low penetrance

  7. ISKS Filtering pipeline 582,235 variants non-synonymous, STOP, essential splice site, frameshifts 54,718 variants No dbSNP ID or allele frequency<0.05, EVS EA population 26,365 variants QUAL>60 and total read depth ≥20 and ≥8 reads with variant allele and ≥20% reads had variant allele 17,001 variants Strand bias (FS)<100 & Positional bias (ReadPosRankSum)>-10 8,701 variants Occurs ≤3 times in cohort 1452 variants Class I GenomeTrax disease mutant AND NOT benign by Condel Class II STOP, FS, essential splice, initiator codon variant Class III Missense, Condel <-0.7, ISKS:EVS>4 Rest

  8. ISKS Filtering pipeline 582,235 variants non-synonymous, STOP, essential splice site, frameshifts 54,718 variants No dbSNP ID or allele frequency<0.05, EVS EA population 26,365 variants CLASS I 86 variants in 85 probands CLASS II 41 variants in 38 probands QUAL>60 and total read depth ≥20 and ≥8 reads with variant allele and ≥20% reads had variant allele 17,001 variants CLASS III 299 variants in 225 probands No pathogenic variation 379 probands Strand bias (FS)<100 & Positional bias (ReadPosRankSum)>-10 8,701 variants • 116/681 (17%) ISKS probands carry 123 Class I or II variants • 302/681 (44%) carry 426 class I-III variants Occurs ≤3 times in cohort 1452 variants Class I GenomeTrax disease mutant AND NOT benign by Condel Class II STOP, FS, essential splice, initiator codon variant Class III Missense, Condel <-0.7, ISKS:EVS>4 Rest

  9. Mutation status and age of cancer onset HR 1.2, 95%CI 0.92-1.56, P=0.008 HR 1.46, 95%CI 0.99-2.16, P=0.026 HR 1.32, 95%CI 1.1-1.6, P<0.0001 HR 1.28, 95%CI 1.1-1.5, P<0.0001 Hazard ratios: Mantel-Haenszel; Curve comparisons: Gehan-Breslow-Wilcoxon

  10. ISKS Filtering pipeline 582,235 variants non-synonymous, STOP, essential splice site, frameshifts 54,718 variants No dbSNP ID or allele frequency<0.05, EVS EA population 26,365 variants • 90 (13%)individuals carry 2+ (214) variants • 24 (4%)individuals carry 3+ (82) variants CLASS I 86 variants in 85 probands CLASS II 41 variants in 38 probands QUAL>60 and total read depth ≥20 and ≥8 reads with variant allele and ≥20% reads had variant allele 17,001 variants CLASS III 299 variants in 225 probands No pathogenic variation 379 probands Strand bias (FS)<100 & Positional bias (ReadPosRankSum)>-10 8,701 variants Occurs ≤3 times in cohort 1452 variants Class I GenomeTrax disease mutant AND NOT benign by Condel Class II STOP, FS, essential splice, initiator codon variant Class III Missense, Condel <-0.7, ISKS:EVS>4 Rest

  11. Polygenic contribution to age of cancer onset * P=0.008 ** P=0.0001 *** P<0.0001 Trend: P<0.0001 Curve comparisons: Logrank for trend; Gehan-Breslow-Wilcoxon for paired comparisons

  12. Enrichment for deleterious variants in the ISKS cohort • 950 case Australian control cohort • 55-80 years of age, selected on high/low bone density • Free of co-morbidity, including cancer • Whole exome panel • To correct for platform bias, compare ratios of deleterious to synonymous variation • Deleterious = FS, stop, ESS, initiator codon variant; or missense variant with Condel score > 0.7

  13. Gene-specific mutation patterns in the ISKS cohort

  14. Gene-specific mutation patterns in the ISKS cohort * CHEK2 * TP53 * CDKN2A * ATM

  15. DNA damage and homologous recombination pathway NBN (11) MRE11A (4) Homologous recombination/TP53 pathway n = 201 (Classes I-III) RAD50 (13) CDKN2A (2) ATM (17) CHEK2 (5) BRCA1 (2) PALB2 (6) FAM175A (4) TP53 (19) ATR (14) BRCA2 (18) BRIP1 (12) RAD51C (1) FANCI/D2 (5/2) TP53BP1 (6) WRAP53 (4) FANC A-C/E-G/L/M (62)

  16. ISKS therapeutic implications PTCH1 LDE225

  17. ISKS Acknowledgements Funding Rainbows for Kate Foundation NHMRC VCA PeterMac Stephen Wong Alex Dobrovic Genomics Core Richard Tothill Aga Borcz University of Queensland Matt Brown Paul Leo kConFab staff Heather Thorne ISKS participating families International Steering Committee Isabelle Ray-Coquard Ajay Puri Study manager – Mandy Ballinger Data Manager – Eveline Niedermayr Research Assistant – Kim Riddell Thomas lab David Goode Tiffany Pang Arcadi Cipponi PeterMac FCC Gillian Mitchell Paul James Mary-Anne Young Alex Lewis

  18. Genetic pathways NBN (8) MRE11A (1) Homologous recombination/TP53 pathway n = 62 (Class I/II) RAD50 (2) ATM (5) CHEK2 (5) BRCA1 (1) PALB2 (2) TP53 (19) ATR (2) BRCA2 (3) BRIP1 (3) RAD51C (1) FANCI/D2 TP53BP1 (1) WRAP53 (-) FANC A-C/E-G/L/M (12)

  19. ISKS Genotypes • 116/681 (17%) ISKS probands carry 123 Class I or II variants • 302/681 (44%) carry 426 class I-III variants • 90 individuals carry 2+ (214) variants • 24 individuals carry 3+ (82) variants

  20. ISKS Phenotypes & FCC referral Clinically suspicious +++ ++ Chomp/LFS + BRCA Other Lynch -like

  21. ISKS Sarcoma subtypes

  22. ISKS gene panel • Agilent Haloplex custom panel of 85-101 gene CDS capture • 681 ISKS probands APC CDH1 EXT1 FANCM MLH3 PMS2 RET SQSTM1 WRN ARID1A CDKN2A EXT2 FH MRE11A POLH RMI1 STK11 WT1 ATM CHEK1 FAM175A IDH1 MSH2 PPARG RMI2 TAF15 XPA ATR CHEK2 FANCA IDH2 MSH3 PRKAR1A RPA3 TGFBR2 XPC AXIN1 DDB2 FANCB KIF1B MSH6 PTCH1 RPA70TNFRSF11AXRCC2 AXIN2 DICER1 FANCC KIT MUTYH PTEN RPS19 TOP1 BARD1 DKC1 FANCD2 LIG1 NBN PTPN11 SDHA TOP3A BLM DNA2 FANCE LIG4 NEIL2 RAD50 SDHB TP53 BRCA1 ERCC2 FANCF MDM2 NF1 RAD51C SDHC TP53BP1 BRCA2 ERCC3 FANCG MEN1 NF2 RAD51L3 SDHD TSC1 BRIP1 ERCC4 FANCI MET PALB2 RB1 SMARCA4 TSC2 BUB1B ERCC5 FANCL MLH1 PMS1 RECQL4 SMARCB1 VHL Batch 1 – genes in black Batch 2 – genes in black & red

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