Background
Methods
Initial discovery cohort
Samples for whole exome sequencing
Whole exome sequencing
Sequence alignment and variant calling
Variant categorization
Association analysis
Bonferroni correction
Segregation analysis
Gene validation
Replication cohort
Whole genome sequencing
Annotation of variants in candidate genes
Variant annotation and filtering
Variant burden analyses
Results
Discovery of candidate risk variants
Variable | Study | ISKSa |
---|---|---|
Sex | 11 female (58%) | – |
Average age of patients | 55.3 years (range: 15–90 years) | – |
Average age of cancer onset | 47.5 years (range: 15–79 years) | 47 years (range: 1 month – 93 years) |
Average age of sarcoma onset | – | 46 years (range: 3–93 years) |
Whole exome sequencing
Variant annotation and filtering
Function | Percentage |
Exonic | 42.45 |
Intronic | 50.74 |
Intergenic | 0.04 |
Upstream/downstream | 0.68 |
Untranslated region | 4.96 |
Other | 1.13 |
Exonic function | Percentage |
Nonsynonymous | 47.61 |
Synonymous | 50.55 |
Stop gain/loss | 0.50 |
Unknown | 1.35 |
Variant identification
Family-based association and segregation analyses
avSNP147 | Chra | Position | Gene | AA change/ Reg. Featureb | Family # | Cancer Outcome | p-valuec | Q-valued | Variant Type | SIFTe | PolyPhen-2 | Family MAFf | MAF 1 K g |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Rare Private Variants | |||||||||||||
– | 8 | 145,773,319 |
ARHGAP39
| G1151A | 3 | Age at onset of cancer | 0.01 | 1.00 | NS | Deleterious | Deleterious | 0.079 | – |
Any Cancer | 0.02 | 1.00 | |||||||||||
Known Private Rare Variants | |||||||||||||
rs191227556 | 16 | 4,606,552 |
C16orf96
| T62C TFh Binding + DNase Footprint + DNase Peak | 2 | Age at onset of cancer | 0.01 | 1.00 | NS/ REG | Deleterious | Deleterious | 0.105 | 0.0002 |
Any Cancer | 0.01 | 1.00 | |||||||||||
rs139741319 | 7 | 20,721,130 |
ABCB5
| TF binding + matched TF motif + DNase peak | 2 | Age at onset of cancer | 0.01 | 1.00 | REG | – | – | 0.105 | 0.0008 |
Any Cancer | 0.01 | 1.00 | |||||||||||
rs139213019 | 1 | 40,929,077 |
ZFP69B
| C1421G | 3 | Age at onset of cancer | 0.01 | 1.00 | NS | Deleterious | Deleterious | 0.079 | 0.0016 |
Any Cancer | 0.02 | 1.00 | |||||||||||
rs116741007 | 4 | 1,348,920 |
UVSSA
| G1063A | 3 | Age at onset of cancer | 0.01 | 1.00 | NS | Deleterious | Deleterious | 0.079 | 0..0040 |
Any Cancer | 0.02 | 1.00 | |||||||||||
rs200706119 | 16 | 66,503,705 |
BEAN1
| C226A | 3 | Age at onset of cancer | 0.01 | 1.00 | NS | Tolerated | – | 0.079 | 0.0050 |
rs139373762 | 1 | 45,224,937 |
KIF2C
| TF Binding + DNase Footprint + DNase Peak | 3 | Age at onset of cancer | 0.01 | 1.00 | REG | – | – | 0.079 | 0.0012 |
Candidate Gene Variants | |||||||||||||
rs45614840 | 16 | 334,543 |
PDIA2
| C356G | 2 | Age at onset of cancer | 0.01 | 1.00 | NS | Deleterious | Deleterious | 0.105 | 0.05 |
Any Cancer | 0.01 | 1.00 |
Validation
Variant burden analyses
Gene of interest | Allele Counts (# NS Variants) ISKSa | Allele Counts (# NS Variants) MGRBb | Odds ratio | p-valuec |
Q-value
d
|
---|---|---|---|---|---|
ABCB5
| 30 (17) | 32 (16) | 1.79 | 0.02 | 0.16 |
ARHGAP39
| 1 (1) | 3 (1) | 2.07 | 0.45 | 1.00 |
BEAN1
| 1 (1) | 0 (0) | 0 | 1 | 1.00 |
C16orf96
| 4 (4) | 12 (9) | 1.81 | 0.296 | 0.237 |
KIF2C
| 0 (0) | 1 (1) | 0 | 1 | 1.00 |
PDIA2
| 5 (5) | 1 (1) | 4.07 | 0.23 | 1.00 |
UVSSA
| 21 (8) | 25 (6) | 1.29 | 0.45 | 1.00 |
ZFP69B
| 2 (2) | 16 (4) | 0.51 | 0.55 | 1.00 |
Gene of interest | Allele Counts (# Reg. Variants) ISKSa | Allele Counts (#Reg. Variants) MGRBb | Odds ratio | p-valuec |
Q-value
d
|
---|---|---|---|---|---|
ABCB5
| 12 (5) | 3 (3) | 4.9 | 0.007 | 0.049 |
ARHGAP39
| 10 (3) | 24 (4) | 1.13 | 0.702 | 1.00 |
BEAN1
| 3 (1) | 1 (1) | 6.11 | 0.10 | 0.800 |
C16orf96
| 58 (3) | 151 (3) | 0.58 | 0.0004 | 0.003 |
KIF2C
| 2 (1) | 9 (1) | 0.45 | 0.52 | 1.00 |
PDIA2
| 10 (1) | 24 (1) | 0.85 | 0.85 | 1.00 |
UVSSA
| 114 (4) | 215 (4) | 1.09 | 0.44 | 1.00 |
ZFP69B
| 0 (0) | 0 (0) | – | – | – |