Genetic risk in sarcoma INTERNATIONAL SARCOMA KINDRED STUDY
Dec 24, 2015
Genetic risk in sarcoma
INTERNATIONAL SARCOMAKINDRED STUDY
ISKS Global
PARTICIPANT
INDIATata Memorial
Hosp
FRANCECentre Claude
Berard
USAHuntsman Cancer Inst
UKMarsden & UCLH
AUSTRALIAPeterMac
Royal Prince AlfredPrince of Wales
Princess AlexandraWesley
Royal AdelaideHollywood Private
CENTRALBiospecimens
LaboratoryDatabase
ISKS GLOBAL STEERING COMMITTEE
BiospecimensLaboratoryDatabase
APPROVED PROJECTS
CANADAVancouver Hosp
NZChristchurch Hosp
BiospecimensLaboratoryDatabase
BiospecimensLaboratoryDatabase
BiospecimensLaboratoryDatabase
BiospecimensLaboratoryDatabase
Local Study Centres
Global Study Centre
ISKS
ISKS families 645 families
207 no family history, 51 uninformative
387 families with cancer historyTP53 related syndromes
9 Classic Li Fraumeni Syndrome58 Chompret LFL19 Birch LFL279 Eeles LFL
Other sarcoma related syndromes1 familial schwannomatosis1 neurofibromatosis2 Gorlin’s syndrome15 other striking pedigrees
Other cancer syndromes1 breast cancer, 2 colorectal cancer
ATM
NBN
RAD50
MRE11A
BRCA1 PALB2
BRCA2 BRIP1
RAD51FANCI/D2
TP53
FANCA-C/E-G/L/M
CHEK2
37/105 (27%) patients carrying 50 cancer predisposition alleles
Screening for heritable cancer genes in sarcoma
Screening for heritable cancer genes in sarcoma
ATM/ATR
NBN
RAD50
MRE11A
BRCA1 PALB2BRIP1BARD1
BRCA2
RAD51FANCI/D2
TP53
FANCA-C/E-G/L/M
CHEK2
6/106
2/106
(19/580)7/106
2/106
38/106 (27%) patients carrying 50 cancer predisposition alleles
1/1062/106
2/106
(0)
(0)
(0)
(0)
TP53 wild-type by MLPA and HRM/Sequencing
TP53 wild-type by MLPA and HRM/Sequencing
* *
*
*
* *
Whole exome sequencing
Genes of interestAffected
Genes of interestAffected
Genes of interestAffected
Sept 2007
Feb 2008
Comparison of the germ cell tumor and the myelodysplasia
JNCI, 1990, 82:221
NEJM, 1990, 322:1425
Clonal i(12p) in both mediastinal GCT and leukemia
Co-expression in leukemic cells of cytokeratin and monocytic markers
DNA Ligase 1• K #2: somatic mutation in LIG1 (T311M, Condel/PolyPhen2 pathogenic)
– Retention of paternal LOF allele (V349M)
• Functions in DNA replication and the base excision repair process– Neil2 involved in BER– Interacts physically with Nbn
• Mutations in LIG1 result in immunodeficiency and increased sensitivity to DNA-damaging agents
• Associated with increased cancer risk– Compound heterozygoyte died of lymphoma age 19– Variants associated with lung cancer risk
• Gene targeting in mice– Required for development– Associated with anemia
Osteoporosis
Rainbows for Kate Foundation
ISKS participants and families
ISKS Australia Steering Committee
ISKS Global Steering Committee
ISKS AustraliaMandy BallingerJess McDonaldKim RiddellBelinda ZielonyJasmine MarKate CroughKate Mahendran
kConFab/ISKS RNsAllison WichtVicki Fennelly
kConFabHeather ThorneEveline NiedermayrLinda WilliamsLana DjandjgavaCarla Osinski
AcknowledgementsPeter MacPaul JamesGillian MitchellMary-Anne Young
Ella ThompsonIan Campbell
Richard Tothill
Maria DoyleJason EllulJason Li
RUNESRapid Understanding of Nucleotide variant Effect Software
STEPHEN KINGSMORE, CENTER FOR PEDIATRIC GENOMIC MEDICINEKANSAS CHILDREN’S MERCY HOSPITAL
Novelty
ENSEMBL
HGMD
dbSNP
Splice effect
ACMG category
Consolidate
Translation impact
Affected genes/transcripts/proteinsNCBI gene
Reference and variant codonsReference and variant AA
HGVS nomenclatureSIFT/POLYPHEN2/BLOSUM/Condel
dbSNP rsID/MAFClinVar cross referenceHGMD cross reference
Splicing/translational effectOMIM cross reference
FrameshiftDomain mapping
Mutations cross referenceMouse Genome DatabaseDECIPHER cross reference
ACMG classification
Category Description Criteria1 Previously reported and recognized
causeHGMD variant disease mutantdbSNP pathogenic clinical significance
2 Novel, pathogenic Loss of initiation, premature or disrupted STOP, whole gene deletion, frameshift, essential splice disruption
3 Novel, may be pathogenic Non-synonymous, in-frame indel, polypyrimidine tract disruption, other splice site variants
4 Novel, probably not pathogenic All variants not in categories 1-3, synonymous, dbSNP MAF>0.02
5 Known neutral -
6 Association with disease, but not expected to be pathogenic
-
Maternal
18
Paternal
1514 16 2616
Neither
114 16
Both(het)
299 2
None homozygous
Nijmegen Breakage Syndrome
Autosomal recessive Fanconi anemia phenotype• Radiosensitivity• Cancer predisposition
-50% incidence <15 years-lymphoid malignancies -brain tumors-rhabdomyosarcoma