Table 1.
Melanoma case/control and replication
| Primary cohort |
TCGA replication cohort |
UK EBF3 replication |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Gene | Method* | No. variants CM cases (n = 273) | No. variants controls (n = 7629) | Pmin | No. variants TCGA CM (n = 379) | No. variants controls (n = 3563) | P | No. variants Sanger CM (n = 132)† | No. variants UK10K (n = 4769) | Joint OR‡ (95% CI) |
| CDKN2A | PTV burden | 5§ | 0 | 6.16 × 10-8‖ | 2 | 0 | .009¶ | – | – | – |
| ACTR8 | C-alpha | 7 | 56 | 2.18 × 10-5 | 5 | 26 | .14 | – | – | – |
| ECHDC1 | C-alpha | 6 | 32 | 3.73 × 10-5 | 1 | 14 | .83 | – | – | – |
| COL11A2 | PTV burden | 4 | 3 | 5.42 × 10-5 | 0 | 4 | .60 | – | – | – |
| DIP2B | C-alpha | 21 | 272 | 7.15 × 10-5 | 4 | 78 | .20 | – | – | – |
| EBF3 | C-alpha | 4 | 14 | 8.22 × 10-5 | 3 | 7 | 4.75 × 10-4 | 2 | 21 | 4.95 (2.35 to 10.41) |
| No. variants OM cases (n = 99) | No. variants controls (n = 7629) | Pmin | No. Variants TCGA OM (n = 47) | No. variants controls (n = 3563) | P | |||||
| BAP1 | PTV burden | 4 | 3 | 3.83 × 10-6 | 1 | 1 | .03 | |||
| IAH1 | C-alpha | 6 | 68 | 2.27 × 10-5 | 0 | 31 | – | |||
| NHLRC3 | C-alpha | 10 | 183 | 6.88 × 10-5 | 0 | 84 | – | |||
| RSRC1 | C-alpha | 5 | 44 | 1.00 × 10-4 | 0 | 18 | – | |||
| PAPOLG | C-alpha | 6 | 47 | 1.00 × 10-4 | 0 | 21 | – | |||
This column represents the statistical test that was used to compute P value; all listed tests were two-sided.
Melanoma kindreds of British ancestry were included to approximate the U.K.10K control collection. The UK replication included 77 cases (66 families) from Leeds, UK, and 56 cases (nine families) from Sydney, Australia. A p.N455S mutation was found in one Leeds family (one of two cases positive for mutation), and a p.G21S mutation was identified in one Sydney family (two of six cases positive for mutation).
Mantel-Haenszel chi-square test P value = 1.37 × 10-5. In the joint burden analysis, we undertook a more conservative stance and censored the second carrier from the Sydney family while including all the noncarriers. Thus, three mutations were detected in 133 total cases, but only two mutation carriers from 132 cases were used in the calculation. CI = confidence interval; CM = cutaneous melanoma; OM = ocular melanoma; TCGA = The Cancer Genome Atlas.
Values in table indicate the number of rare (MAF < 0.01) variants.
Genome-wide statistically significant.
Identical test used in both primary and TCGA replication cohorts for each gene (eg, PTV burden for CDKN2A in both primary and TCGA replication cohorts).