international sarcoma kindred study: first gene screens
DESCRIPTION
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 +. - PowerPoint PPT PresentationTRANSCRIPT
INTERNATIONAL SARCOMA KINDRED STUDY:
FIRST GENE SCREENS
ISKS cohort
ISKS hereditary cancer syndromes
658 ISKS families
109Uninformative
104No cancer in
1o/2o rels
337No defined syndrome
108Recognised syndrome
69 Clinically
suspicious
268Not
suspicious
56Chomp/
LFS
21BRCA
17Lynch like
14Other
16++
42+
11+++
658 ISKS families
109Uninformative
104No cancer in
1o/2o rels
337No defined syndrome
108Recognised syndrome
69 Clinically
suspicious
268Not
suspicious
56Chomp/
LFS
21BRCA
17Lynch like
14Other
16++
42+
11+++
19% of these families were referred to a familial cancer clinic
ISKS hereditary cancer syndromes
Cancer genes: frequency and penetrance
Commonlow penetrance
Rarehigh penetrance
Commonlow penetrance
Rarehigh penetrance
Cancer genes: frequency and penetrance
QUAL>60 and total read depth ≥20 and ≥8 reads with variant allele and ≥20% reads had
variant allele17,001 variants
No dbSNP ID or allele frequency<0.05, EVS EA population
26,365 variants
Class IGenomeTrax disease
mutant ANDNOT benign by Condel
Class IISTOP, FS, essential splice, initiator codon
variant
Class IIIMissense, Condel <-
0.7, ISKS:EVS>4
ISKS Filtering pipeline
582,235 variants
non-synonymous, STOP, essential splice site, frameshifts
54,718 variants
Strand bias (FS)<100 & Positional bias (ReadPosRankSum)>-10
8,701 variants
Occurs ≤3 times in cohort1452 variants
Rest
QUAL>60 and total read depth ≥20 and ≥8 reads with variant allele and ≥20% reads had
variant allele17,001 variants
No dbSNP ID or allele frequency<0.05, EVS EA population
26,365 variants
Class IGenomeTrax disease
mutant ANDNOT benign by Condel
Class IISTOP, FS, essential splice, initiator codon
variant
Class IIIMissense, Condel <-
0.7, ISKS:EVS>4
582,235 variants
non-synonymous, STOP, essential splice site, frameshifts
54,718 variants
Strand bias (FS)<100 & Positional bias (ReadPosRankSum)>-10
8,701 variants
Occurs ≤3 times in cohort1452 variants
Rest
ISKS Filtering pipeline
CLASS I
86 variants in 85 probands
CLASS II
41 variants in 38 probands
CLASS III
299 variants in 225 probands
No pathogenic variation
379 probands
•116/681 (17%) ISKS probands carry 123 Class I or II variants
•302/681 (44%) carry 426 class I-III variants
Mutation status and age of cancer onset
HR 1.28, 95%CI 1.1-1.5, P<0.0001
HR 1.46, 95%CI 0.99-2.16, P=0.026 HR 1.2, 95%CI 0.92-1.56, P=0.008
HR 1.32, 95%CI 1.1-1.6, P<0.0001
Hazard ratios: Mantel-Haenszel; Curve comparisons: Gehan-Breslow-Wilcoxon
Median tumor latency
Nil 51y
Class I 40y
Class II 41.5y
Class III 42y
All 42y
QUAL>60 and total read depth ≥20 and ≥8 reads with variant allele and ≥20% reads had
variant allele17,001 variants
No dbSNP ID or allele frequency<0.05, EVS EA population
26,365 variants
Class IGenomeTrax disease
mutant ANDNOT benign by Condel
Class IISTOP, FS, essential splice, initiator codon
variant
Class IIIMissense, Condel <-
0.7, ISKS:EVS>4
582,235 variants
non-synonymous, STOP, essential splice site, frameshifts
54,718 variants
Strand bias (FS)<100 & Positional bias (ReadPosRankSum)>-10
8,701 variants
Occurs ≤3 times in cohort1452 variants
Rest
ISKS Filtering pipeline
•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
CLASS III
299 variants in 225 probands
No pathogenic variation
379 probands
Polygenic contribution to age of cancer onset
Curve comparisons: Logrank for trend; Gehan-Breslow-Wilcoxon for paired comparisons
Number Median tumor latency
Nil 347 51y
1 210 44y*
2 67 37y***
3+ 23 36y**
TP53 19 36y
* P=0.008** P=0.0001*** P<0.0001
Trend: P<0.0001
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
Gene-specific mutation patterns in the ISKS cohort
Gene-specific mutation patterns in the ISKS cohort
*
*
**
CHEK2
TP53
CDKN2A
ATM
ATM(17)
NBN(11)
RAD50(13)
MRE11A(4)
BRCA1(2)
PALB2(6)
BRCA2(18)
BRIP1(12)
RAD51C(1)
FANCI/D2(5/2)
TP53(19)
FANCA-C/E-G/L/M
(62)
CHEK2(5)
Homologous recombination/TP53 pathwayn = 201 (Classes I-III)
DNA damage and homologous recombination pathway
ATR(14)
TP53BP1(6)
FAM175A(4)
WRAP53(4)
CDKN2A(2)
LDE225
PTCH1
ISKS therapeutic implications
ISKS AcknowledgementsISKS participating families
International Steering CommitteeIsabelle Ray-CoquardAjay Puri
Study manager – Mandy BallingerData Manager – Eveline NiedermayrResearch Assistant – Kim Riddell
Thomas labDavid GoodeTiffany PangArcadi Cipponi
PeterMac FCCGillian MitchellPaul JamesMary-Anne YoungAlex Lewis
FundingRainbows for Kate FoundationNHMRCVCA
PeterMacStephen WongAlex Dobrovic
Genomics CoreRichard TothillAga Borcz
University of QueenslandMatt BrownPaul Leo
kConFab staffHeather Thorne
ATM(5)
NBN(8)
MRE11A(1)
BRCA1(1)
PALB2(2)
BRCA2(3)
BRIP1(3)
RAD51C(1)
FANCI/D2
TP53(19)
FANCA-C/E-G/L/M
(12)
CHEK2(5)
Homologous recombination/TP53 pathwayn = 62 (Class I/II)
Genetic pathways
ATR(2)
TP53BP1(1)
WRAP53(-)
RAD50(2)
• 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
ISKS Genotypes
ISKS Phenotypes & FCC referral
Clinically suspicious
Chomp/LFS
BRCA
Lynch-like
Other
+
++
+++
ISKS Sarcoma subtypes
ISKS gene panel
APC CDH1 EXT1 FANCM MLH3 PMS2 RET SQSTM1 WRNARID1A CDKN2A EXT2 FH MRE11A POLH RMI1 STK11 WT1ATM CHEK1 FAM175A IDH1 MSH2 PPARG RMI2 TAF15 XPAATR CHEK2 FANCA IDH2 MSH3 PRKAR1A RPA3 TGFBR2 XPCAXIN1 DDB2 FANCB KIF1B MSH6 PTCH1 RPA70 TNFRSF11AXRCC2AXIN2 DICER1 FANCC KIT MUTYH PTEN RPS19 TOP1BARD1 DKC1 FANCD2 LIG1 NBN PTPN11 SDHA TOP3ABLM DNA2 FANCE LIG4 NEIL2 RAD50 SDHB TP53BRCA1 ERCC2 FANCF MDM2 NF1 RAD51C SDHC TP53BP1BRCA2 ERCC3 FANCG MEN1 NF2 RAD51L3 SDHD TSC1BRIP1 ERCC4 FANCI MET PALB2 RB1 SMARCA4 TSC2BUB1B ERCC5 FANCL MLH1 PMS1 RECQL4 SMARCB1 VHL
Batch 1 – genes in blackBatch 2 – genes in black & red
•Agilent Haloplex custom panel of 85-101 gene CDS capture
•681 ISKS probands