Table 1.
Individual tumour mutational signatures (TMS) identified to be associated with a hereditary CRC group from the analysis of 737 CRCs. Individual TMS with an AUC>0.90 and/or mean difference >10pp are shown, as well as the best combination of TMS determined using forward selection applied to the discovery group. The robustness of these results are illustrated by the accuracy obtained when applied to an independent validation set, and when our MMRp and MMRd control groups were replaced with TCGA MMRp and MMRd CRCs.
| Comparison | Cohort | TMS | AUC (95% CI) | LD | Mean Diff | p-value adjusted | Carriers | Non-carriers |
|---|---|---|---|---|---|---|---|---|
| MUTYH v. non-MUTYH | Discovery | SBS18 | 0.960 (0.864–1.000) | 1.108 | 0.218 | 5.46E-13 | 8 | 128 |
| Discovery | SBS36 | 0.936 (0.816–1.000) | 2.992 | 0.337 | 8.57E-38 | 8 | 128 | |
| Discovery | SBS18, SBS36 | 1.000 (0.910–1.000) | 20.81 | 0.556 | 4.29E-58 | 8 | 128 | |
| Validation | SBS18, SBS36 | 1.000 * | 10.99 | 0.529 | 7.40E-38 | 4 | 90 | |
| Combined | SBS18, SBS36 | 1.000 (0.960–1.000) | 16.17 | 0.547 | 4.60E-98 | 12 | 218 | |
| MUTYH v. TCGA | TCGA Validation | SBS18, SBS36 | 1.000 (0.960–1.000) | 14.551 | 0.535 | 5.03E-127 | 12 | 498 |
|
| ||||||||
| MMRd v. MMRp | Discovery | ID2 | 0.974 (0.934–1.000) | 5.161 | 0.395 | 1.76E-24 | 30 | 112 |
| L K v. M W C | Discovery | ID7 | 0.947 (0.890–1.000) | 2.266 | 0.213 | 2.81E-19 | 30 | 112 |
| Discovery | SBS20 | 0.950 (0.894–1.000) | 2.585 | 0.078 | 3.29E-31 | 30 | 112 | |
| Discovery | ID2,ID7 | 1.000 (0.980–1.000) | 13.85 | 0.608 | 3.96E-42 | 30 | 112 | |
| Validation | ID2,ID7 | 0.985 (0.953–1.000) | 7.633 | 0.6 | 2.12E-23 | 28 | 68 | |
| Combined | ID2,ID7 | 0.994 (0.981–1.000) | 10.5 | 0.603 | 3.38E-66 | 58 | 180 | |
| TCGA-MMRd v. TCGA-MMRp | TCGA Validation | ID2,ID7 | 0.995 (0.981-1.000) | 25.989 | 0.784 | 9.86E-149 | 52 | 446 |
|
| ||||||||
| MMR PV carrier v. MMRp | Discovery | ID2 | 0.986 (0.946–1.000) | 7.102 | 0.434 | 1.10E-18 | 17 | 112 |
| Discovery | ID7 | 0.915 (0.822–1.000) | 2.025 | 0.143 | 7.66E-08 | 17 | 112 | |
| Discovery | SBS15 | 0.861 (0.747–0.976) | 1.131 | 0.113 | 5.66E-06 | 17 | 112 | |
| Discovery | SBS20 | 0.912 (0.817–1.000) | 1.54 | 0.061 | 4.91E-20 | 17 | 112 | |
| Discovery | ID2,ID7 | 1.000 (0.960–1.000) | 13.21 | 0.578 | 2.52E-27 | 17 | 112 | |
| Validation | ID2,ID7 | 0.985 (0.943–1.000) | 8.14 | 0.614 | 5.67E-16 | 16 | 68 | |
| Combined | ID2,ID7 | 0.994 (0.976–1.000) | 10.53 | 0.594 | 1.54E-44 | 33 | 180 | |
| L v. TCGA-MMRp | TCGA Validation | ID2,ID7 | 0.994 (0.976–1.000) | 26.526 | 0.775 | 2.51E-111 | 33 | 446 |
|
| ||||||||
| MMR PV carrier v. MLH1 methylated | Discovery | ID12 | 0.952 (0.875–1.000) | 3.512 | 0.071 | 1.64E-04 | 17 | 13 |
| L v. K | Discovery | SBS1 | 0.817 (0.665–0.969) | 0.826 | 0.155 | 1 | 17 | 13 |
| Validation | SBS1 | 0.789 (0.621–0.957) | 0.727 | 0.143 | 1 | 16 | 12 | |
| Combined | SBS1 | 0.805 (0.694–0.916) | 0.759 | 0.149 | 2.03E-02 | 33 | 25 | |
| L v. TCGA-MMRd | TCGA Validation | SBS1 | 0.837 (0.743–0.931) | 0.979 | 0.163 | 3.21E-06 | 33 | 52 |
M= MMRp CRCs that are from biallelic MUTYH PV carriers (M01-M12)
W= MMRp CRCs that are from monoallelic MUTYH PV carriers (W01-W09)
L= MMRd CRCs from people with MLH1, MSH2 or MSH6 gene mutations (MMR PV carrier; L01-L43)
K= MMRd control CRCs with evidence of MLH1 gene promoter hypermethylation (K01-K25)
C= MMRp control CRCs from the ACCFR (C01-C162)
* Accurate CI estimates are not available for comparisons with less than 5 samples in one group.