Supplementary Tables

Supplementary Table S1: Preselected miRNAs used in feature selection Univariate Cox proportional hazards regression analysis of the endpoint freedom from recurrence in the training set (DKTK-ROG sample) allowed the pre-selection of 524 miRNAs (P< 0.5), which were used in the feature selection. P-value was derived from log-rank test. miRNA p-value miRNA p-value miRNA p-value miRNA p-value hsa-let-7g-3p 0.0001520 hsa-miR-1304-3p 0.0490161 hsa-miR-7108-5p 0.1263245 hsa-miR-6865-5p 0.2073121 hsa-miR-6825-3p 0.0004257 hsa-miR-4298 0.0506194 hsa-miR-4453 0.1270967 hsa-miR-6893-5p 0.2120664 hsa-miR-668-3p 0.0005188 hsa-miR-484 0.0518625 hsa-miR-200a-5p 0.1276345 hsa-miR-25-3p 0.2123829 hsa-miR-3622b-3p 0.0005885 hsa-miR-6851-3p 0.0531446 hsa-miR-6090 0.1278692 hsa-miR-3189-5p 0.2136060 hsa-miR-6885-3p 0.0006452 hsa-miR-1276 0.0557418 hsa-miR-148b-3p 0.1279811 hsa-miR-6073 0.2139702 hsa-miR-6875-3p 0.0008188 hsa-miR-3173-3p 0.0559962 hsa-miR-4425 0.1288330 hsa-miR-765 0.2141536 hsa-miR-487b-5p 0.0011381 hsa-miR-650 0.0564616 hsa-miR-6798-3p 0.1293342 hsa-miR-338-5p 0.2153079 hsa-miR-210-5p 0.0012316 hsa-miR-6133 0.0571407 hsa-miR-4472 0.1300006 hsa-miR-6806-5p 0.2173515 hsa-miR-1470 0.0012822 hsa-miR-4701-5p 0.0571720 hsa-miR-4465 0.1304841 hsa-miR-98-5p 0.2184947 hsa-miR-6890-3p 0.0016539 hsa-miR-202-3p 0.0575741 hsa-miR-514b-5p 0.1308790 hsa-miR-500a-3p 0.2185577 hsa-miR-6511b-3p 0.0017165 hsa-miR-4733-5p 0.0616138 hsa-miR-378c 0.1317442 hsa-miR-4515 0.2187539 hsa-miR-7109-3p 0.0021381 hsa-miR-595 0.0629350 hsa-miR-3121-3p 0.1319386 hsa-miR-4510 0.2194305 hsa-miR-640 0.0033118 hsa-miR-4462 0.0633754 hsa-miR-6743-3p 0.1332837 hsa-miR-146a-5p 0.2220503 hsa-miR-6820-3p 0.0036195 hsa-miR-6763-5p 0.0636346 hsa-miR-1296-5p 0.1352142 hsa-miR-200b-3p 0.2245329 hsa-miR-3617-3p 0.0040518 hsa-miR-1238-3p 0.0638492 hsa-miR-1229-5p 0.1354426 hsa-miR-1273e 0.2247443 hsa-let-7d-3p 0.0040669 hsa-miR-200b-5p 0.0643827 hsa-miR-3607-5p 0.1358297 hsa-miR-181d-5p 0.2254029 hsa-miR-7152-5p 0.0041095 hsa-miR-3609 0.0669743 hsa-miR-3607-3p 0.1365370 hsa-miR-5572 0.2256737 hsa-miR-449b-3p 0.0044936 hsa-miR-2277-3p 0.0687210 hsa-miR-887-3p 0.1366652 hsa-miR-378g 0.2276769 hsa-miR-1227-3p 0.0047357 hsa-miR-4763-5p 0.0720451 hsa-miR-452-5p 0.1440784 hsa-miR-3189-3p 0.2301775 hsa-miR-1273d 0.0060961 hsa-miR-7111-5p 0.0730786 hsa-miR-4478 0.1463108 hsa-miR-758-5p 0.2320042 hsa-miR-3940-3p 0.0071343 hsa-miR-4428 0.0740150 hsa-miR-770-5p 0.1485178 hsa-miR-6730-5p 0.2331420 hsa-miR-6792-3p 0.0078134 hsa-miR-6840-3p 0.0759541 hsa-miR-140-3p 0.1500966 hsa-miR-1-3p 0.2372861 hsa-miR-7161-3p 0.0078813 hsa-miR-4455 0.0775395 hsa-miR-6812-3p 0.1518200 hsa-miR-605-5p 0.2396612 hsa-miR-6722-5p 0.0079627 hsa-miR-2117 0.0776026 hsa-miR-664a-3p 0.1521388 hsa-miR-4655-3p 0.2407594 hsa-miR-1910-5p 0.0086288 hsa-miR-494-3p 0.0786895 hsa-miR-1181 0.1533878 hsa-miR-6800-5p 0.2414789 hsa-miR-6509-5p 0.0087440 hsa-miR-18a-5p 0.0797662 hsa-miR-4746-3p 0.1547788 hsa-miR-6088 0.2420315 hsa-miR-204-5p 0.0096105 hsa-miR-5708 0.0799330 hsa-miR-1224-5p 0.1553392 hsa-miR-4685-5p 0.2422472 hsa-miR-6804-3p 0.0096618 hsa-miR-6752-3p 0.0805763 hsa-miR-128-1-5p 0.1556776 hsa-miR-6748-5p 0.2423384 hsa-miR-939-3p 0.0109262 hsa-miR-10a-5p 0.0814598 hsa-miR-616-3p 0.1565544 hsa-miR-4731-3p 0.2427330 hsa-miR-4306 0.0117792 hsa-miR-328-3p 0.0817575 hsa-miR-1908-3p 0.1581024 hsa-miR-3935 0.2429832 hsa-miR-3174 0.0141084 hsa-miR-92b-3p 0.0822815 hsa-miR-142-5p 0.1582806 hsa-miR-2467-3p 0.2441518 hsa-miR-4732-5p 0.0147261 hsa-miR-3162-5p 0.0839691 hsa-miR-4632-5p 0.1588593 hsa-miR-513c-5p 0.2444128 hsa-miR-33b-3p 0.0156521 hsa-miR-4280 0.0841550 hsa-miR-4449 0.1597510 hsa-miR-623 0.2445756 hsa-miR-6508-5p 0.0158996 hsa-miR-1539 0.0867762 hsa-miR-1183 0.1605472 hsa-miR-4767 0.2445884 hsa-miR-4324 0.0165290 hsa-miR-186-5p 0.0872225 hsa-miR-1291 0.1621822 hsa-miR-574-5p 0.2448785 hsa-miR-590-5p 0.0165776 hsa-miR-4642 0.0876855 hsa-miR-6500-5p 0.1635955 hsa-miR-4322 0.2453192 hsa-miR-6784-3p 0.0166261 hsa-miR-615-3p 0.0879593 hsa-miR-4648 0.1638468 hsa-miR-3202 0.2458438 hsa-miR-885-5p 0.0176496 hsa-miR-6876-5p 0.0891828 hsa-miR-6872-5p 0.1646751 hsa-miR-4257 0.2466355 hsa-miR-6821-5p 0.0184064 hsa-miR-708-5p 0.0897671 hsa-miR-762 0.1652679 hsa-miR-6851-5p 0.2479639 hsa-miR-7155-3p 0.0200061 hsa-miR-711 0.0898413 hsa-miR-5088-5p 0.1652707 hsa-miR-532-5p 0.2487441 hsa-miR-195-3p 0.0203311 hsa-miR-3137 0.0926017 hsa-miR-6753-3p 0.1657836 hsa-miR-6722-3p 0.2494773 hsa-miR-185-5p 0.0227247 hsa-miR-6865-3p 0.0963720 hsa-miR-6801-3p 0.1674969 hsa-miR-6165 0.2501110 hsa-miR-6787-3p 0.0227996 hsa-miR-6775-3p 0.0968004 hsa-miR-184 0.1679089 hsa-miR-6882-5p 0.2503938 hsa-miR-6747-5p 0.0237232 hsa-miR-4530 0.0981749 hsa-miR-23a-5p 0.1679222 hsa-miR-6886-5p 0.2513879 hsa-miR-6511a-3p 0.0238634 hsa-miR-663b 0.0995187 hsa-miR-101-3p 0.1680510 hsa-miR-492 0.2518110 hsa-miR-4506 0.0250136 hsa-miR-6837-5p 0.0997487 hsa-miR-5580-3p 0.1709154 hsa-miR-148a-3p 0.2534658 hsa-miR-191-3p 0.0252090 hsa-miR-4657 0.1002823 hsa-miR-6126 0.1714707 hsa-miR-1913 0.2545273 hsa-miR-4644 0.0254266 hsa-miR-429 0.1019673 hsa-miR-181b-5p 0.1716146 hsa-miR-550a-3-5p 0.2554465 hsa-miR-6730-3p 0.0286103 hsa-miR-301a-3p 0.1028710 hsa-miR-6858-3p 0.1729173 hsa-miR-6862-5p 0.2563177 hsa-miR-7108-3p 0.0286443 hsa-miR-1273h-5p 0.1041604 hsa-miR-874-3p 0.1735055 hsa-miR-4655-5p 0.2572530 hsa-miR-3660 0.0292502 hsa-miR-30c-1-3p 0.1054130 hsa-miR-1233-5p 0.1736421 hsa-miR-4725-3p 0.2582799 hsa-miR-4323 0.0292906 hsa-miR-4753-5p 0.1067460 hsa-miR-6778-5p 0.1745063 hsa-miR-422a 0.2597447 hsa-miR-3976 0.0293703 hsa-miR-1909-5p 0.1078986 hsa-miR-328-5p 0.1755199 hsa-miR-4421 0.2598836 hsa-let-7b-3p 0.0299364 hsa-miR-133b 0.1083123 hsa-miR-365b-5p 0.1800151 hsa-miR-3155b 0.2600660 hsa-miR-3972 0.0313027 hsa-miR-6848-3p 0.1100985 hsa-miR-4259 0.1818164 hsa-miR-6125 0.2610979 hsa-miR-4468 0.0324435 hsa-miR-548q 0.1103041 hsa-miR-130b-3p 0.1823601 hsa-miR-6847-5p 0.2618588 hsa-miR-4430 0.0339590 hsa-miR-7113-5p 0.1103884 hsa-miR-29c-5p 0.1827272 hsa-miR-6791-5p 0.2618956 hsa-miR-6800-3p 0.0362758 hsa-miR-425-3p 0.1130173 hsa-miR-378d 0.1866668 hsa-miR-4436b-3p 0.2620868 hsa-miR-4451 0.0363388 hsa-miR-6756-3p 0.1133662 hsa-miR-6873-5p 0.1883127 hsa-miR-339-3p 0.2621292 hsa-miR-4312 0.0368500 hsa-miR-6880-3p 0.1134722 hsa-miR-664b-5p 0.1916503 hsa-miR-141-3p 0.2628940 hsa-miR-378f 0.0389967 hsa-miR-3679-5p 0.1136289 hsa-miR-6777-3p 0.1938001 hsa-miR-516b-5p 0.2638307 hsa-miR-1273g-5p 0.0395595 hsa-miR-1237-3p 0.1148857 hsa-miR-1228-5p 0.1950725 hsa-miR-7150 0.2642509 hsa-miR-6877-3p 0.0413089 hsa-miR-3926 0.1155312 hsa-miR-99b-3p 0.1955799 hsa-miR-3151-3p 0.2646335 hsa-miR-6889-3p 0.0417185 hsa-miR-3154 0.1163788 hsa-miR-6781-5p 0.1963350 hsa-miR-4769-5p 0.2648458 hsa-miR-4695-3p 0.0424169 hsa-miR-6809-5p 0.1171788 hsa-miR-4497 0.1977408 hsa-miR-6796-3p 0.2663793 hsa-miR-1910-3p 0.0434879 hsa-miR-206 0.1174973 hsa-miR-30b-3p 0.2005012 hsa-miR-4634 0.2663950 hsa-miR-6515-3p 0.0443939 hsa-miR-1273h-3p 0.1176645 hsa-miR-4728-3p 0.2054719 hsa-miR-6758-5p 0.2722472 hsa-miR-4800-3p 0.0444738 hsa-miR-378e 0.1189653 hsa-miR-4282 0.2057643 hsa-miR-4538 0.2742868 hsa-miR-631 0.0462931 hsa-miR-1287-5p 0.1234996 hsa-miR-200a-3p 0.2069192 hsa-miR-133a-3p 0.2748945 hsa-miR-4441 0.0471482 hsa-miR-6516-3p 0.1254558 hsa-miR-3678-3p 0.2069721 hsa-miR-106b-5p 0.2751335 miRNA p-value miRNA p-value miRNA p-value miRNA p-value hsa-miR-4701-3p 0.2757559 hsa-miR-4800-5p 0.3389165 hsa-miR-483-5p 0.3982010 hsa-miR-769-3p 0.4622322 hsa-miR-4539 0.2772361 hsa-miR-4444 0.3390121 hsa-miR-4458 0.3983281 hsa-miR-26b-5p 0.4657563 hsa-miR-6819-3p 0.2773291 hsa-miR-6825-5p 0.3397772 hsa-miR-659-3p 0.3988127 hsa-miR-489-3p 0.4673496 hsa-miR-610 0.2775115 hsa-miR-135b-5p 0.3431898 hsa-miR-1207-5p 0.3988137 hsa-miR-4633-5p 0.4680045 hsa-miR-5006-5p 0.2776556 hsa-miR-423-5p 0.3433266 hsa-miR-4311 0.4000437 hsa-miR-8485 0.4684670 hsa-miR-330-3p 0.2787079 hsa-miR-144-3p 0.3437170 hsa-miR-6829-5p 0.4009580 hsa-miR-6861-5p 0.4689076 hsa-miR-1299 0.2787134 hsa-miR-6850-5p 0.3437688 hsa-miR-3663-3p 0.4058370 hsa-miR-7846-3p 0.4697262 hsa-miR-6766-3p 0.2788320 hsa-miR-1285-3p 0.3437961 hsa-miR-6788-5p 0.4065287 hsa-miR-4792 0.4722690 hsa-miR-4750-3p 0.2795178 hsa-miR-345-5p 0.3447189 hsa-miR-5195-5p 0.4068506 hsa-miR-664b-3p 0.4726302 hsa-miR-3620-3p 0.2803378 hsa-miR-3180-5p 0.3450154 hsa-miR-4743-5p 0.4071310 hsa-miR-3141 0.4738397 hsa-miR-4715-5p 0.2819552 hsa-miR-6762-5p 0.3461694 hsa-miR-933 0.4077111 hsa-miR-6834-3p 0.4760892 hsa-miR-93-5p 0.2836876 hsa-miR-6516-5p 0.3468279 hsa-miR-4317 0.4078686 hsa-miR-4429 0.4765072 hsa-miR-146b-5p 0.2853212 hsa-miR-760 0.3487637 hsa-miR-4769-3p 0.4085797 hsa-miR-4717-3p 0.4789832 hsa-miR-1301-5p 0.2857640 hsa-miR-4433a-5p 0.3497714 hsa-miR-3605-5p 0.4094209 hsa-miR-4261 0.4794872 hsa-miR-4676-5p 0.2866471 hsa-miR-151b 0.3498465 hsa-miR-10b-3p 0.4097002 hsa-miR-6739-5p 0.4795600 hsa-miR-3689a-5p 0.2871961 hsa-miR-197-3p 0.3501618 hsa-miR-31-5p 0.4134444 hsa-miR-7515 0.4796186 hsa-miR-200c-3p 0.2877486 hsa-miR-4498 0.3556529 hsa-miR-320c 0.4140729 hsa-miR-6787-5p 0.4806692 hsa-miR-4481 0.2885148 hsa-miR-5196-5p 0.3568088 hsa-miR-3122 0.4145644 hsa-miR-3162-3p 0.4819271 hsa-miR-3667-5p 0.2909124 hsa-miR-601 0.3579403 hsa-miR-6833-5p 0.4146008 hsa-miR-6769a-5p 0.4827356 hsa-miR-4651 0.2909279 hsa-miR-6763-3p 0.3580989 hsa-miR-374a-5p 0.4178368 hsa-miR-6074 0.4840659 hsa-miR-660-5p 0.2910990 hsa-miR-1295a 0.3585605 hsa-miR-5187-5p 0.4186474 hsa-miR-8063 0.4852187 hsa-miR-221-3p 0.2922822 hsa-miR-6132 0.3585949 hsa-miR-526b-5p 0.4197979 hsa-miR-320a 0.4852946 hsa-miR-5703 0.2937636 hsa-miR-4489 0.3593935 hsa-miR-4535 0.4199090 hsa-miR-6737-5p 0.4867689 hsa-miR-7162-3p 0.2943071 hsa-miR-193a-3p 0.3596357 hsa-miR-6859-5p 0.4219311 hsa-miR-28-5p 0.4875054 hsa-miR-6870-5p 0.2944645 hsa-miR-658 0.3612695 hsa-miR-498 0.4221811 hsa-miR-4476 0.4875920 hsa-miR-7847-3p 0.2944758 hsa-miR-4675 0.3612755 hsa-miR-150-3p 0.4228587 hsa-miR-1225-5p 0.4888175 hsa-miR-4531 0.2947083 hsa-miR-4665-3p 0.3618972 hsa-miR-3150b-5p 0.4233146 hsa-miR-572 0.4890931 hsa-miR-126-5p 0.2964879 hsa-miR-4486 0.3623247 hsa-miR-4313 0.4237833 hsa-miR-6720-3p 0.4925476 hsa-miR-30c-2-3p 0.2971810 hsa-miR-3150b-3p 0.3630354 hsa-miR-20b-5p 0.4243308 hsa-miR-6716-5p 0.4926859 hsa-miR-19a-3p 0.2981113 hsa-miR-1185-1-3p 0.3634745 hsa-miR-127-3p 0.4251458 hsa-miR-645 0.4939564 hsa-miR-6831-5p 0.2988423 hsa-miR-142-3p 0.3648244 hsa-miR-4487 0.4261015 hsa-miR-4514 0.4961114 hsa-miR-4274 0.2990448 hsa-miR-4778-5p 0.3650561 hsa-miR-504-3p 0.4282119 hsa-miR-3194-5p 0.4983921 hsa-miR-9500 0.3007981 hsa-miR-155-5p 0.3651904 hsa-miR-4327 0.4288066 hsa-miR-6774-5p 0.4992132 hsa-miR-4783-3p 0.3008272 hsa-miR-575 0.3668855 hsa-miR-1587 0.4295395 hsa-miR-99b-5p 0.4993586 hsa-miR-187-5p 0.3030038 hsa-miR-3621 0.3672843 hsa-miR-324-5p 0.4297447 hsa-miR-663a 0.3031383 hsa-miR-4749-3p 0.3681453 hsa-miR-4695-5p 0.4300781 hsa-miR-6085 0.3033238 hsa-miR-1306-3p 0.3688894 hsa-miR-224-5p 0.4315439 hsa-miR-6813-3p 0.3044894 hsa-miR-17-3p 0.3699834 hsa-miR-1234-3p 0.4323802 hsa-miR-8071 0.3053416 hsa-miR-193b-3p 0.3699881 hsa-miR-939-5p 0.4353144 hsa-miR-324-3p 0.3060355 hsa-miR-583 0.3745997 hsa-miR-30e-5p 0.4357760 hsa-miR-7641 0.3066042 hsa-miR-1471 0.3747597 hsa-miR-4691-5p 0.4360742 hsa-miR-1307-5p 0.3081795 hsa-miR-513b-5p 0.3750780 hsa-miR-4748 0.4363826 hsa-miR-6802-5p 0.3082514 hsa-miR-6892-5p 0.3761181 hsa-miR-4660 0.4379037 hsa-miR-4534 0.3099680 hsa-miR-6798-5p 0.3774333 hsa-miR-1972 0.4380598 hsa-miR-6836-3p 0.3114869 hsa-miR-6890-5p 0.3776938 hsa-miR-30d-5p 0.4383315 hsa-miR-361-5p 0.3116489 hsa-miR-197-5p 0.3792933 hsa-miR-3945 0.4387155 hsa-miR-1228-3p 0.3123458 hsa-miR-4698 0.3806729 hsa-miR-140-5p 0.4406824 hsa-miR-3185 0.3128071 hsa-miR-1303 0.3818184 hsa-miR-1273c 0.4420271 hsa-miR-4508 0.3142474 hsa-miR-6134 0.3819648 hsa-miR-5587-5p 0.4427138 hsa-miR-4787-3p 0.3149027 hsa-miR-508-5p 0.3825765 hsa-miR-921 0.4428799 hsa-miR-4448 0.3164817 hsa-miR-4281 0.3839601 hsa-miR-7107-5p 0.4429626 hsa-miR-6785-5p 0.3184853 hsa-miR-5739 0.3839771 hsa-miR-3195 0.4430519 hsa-miR-4294 0.3196913 hsa-miR-4433b-3p 0.3841318 hsa-miR-3922-5p 0.4431361 hsa-miR-6790-3p 0.3210339 hsa-miR-6867-5p 0.3855275 hsa-miR-4433a-3p 0.4437860 hsa-miR-6510-5p 0.3229344 hsa-miR-3653-3p 0.3856377 hsa-miR-8088 0.4444357 hsa-miR-630 0.3261865 hsa-miR-1288-3p 0.3856562 hsa-miR-373-5p 0.4446334 hsa-miR-4776-5p 0.3265320 hsa-miR-3622b-5p 0.3872925 hsa-miR-654-5p 0.4470611 hsa-miR-4269 0.3267446 hsa-miR-1343-5p 0.3880427 hsa-miR-3648 0.4478767 hsa-miR-431-5p 0.3285992 hsa-miR-6775-5p 0.3892515 hsa-miR-6760-5p 0.4482549 hsa-miR-6127 0.3286563 hsa-miR-4758-5p 0.3899415 hsa-miR-196a-5p 0.4487262 hsa-miR-6797-3p 0.3295605 hsa-miR-4668-5p 0.3907103 hsa-miR-5585-3p 0.4498612 hsa-miR-4418 0.3309011 hsa-miR-6815-5p 0.3909818 hsa-miR-1261 0.4503372 hsa-miR-29c-3p 0.3315424 hsa-miR-222-3p 0.3918051 hsa-miR-8089 0.4504288 hsa-miR-6891-5p 0.3317906 hsa-miR-493-3p 0.3918729 hsa-miR-4436b-5p 0.4505025 hsa-miR-1203 0.3329465 hsa-miR-99a-5p 0.3925939 hsa-miR-425-5p 0.4524247 hsa-miR-1290 0.3330099 hsa-miR-378b 0.3938166 hsa-miR-1249-3p 0.4525013 hsa-miR-4459 0.3336680 hsa-miR-6782-5p 0.3950183 hsa-miR-1246 0.4527264 hsa-miR-6799-5p 0.3338938 hsa-miR-1285-5p 0.3966182 hsa-miR-6804-5p 0.4533018 hsa-miR-4793-3p 0.3356465 hsa-miR-223-3p 0.3968884 hsa-miR-365a-5p 0.4540624 hsa-miR-519e-5p 0.3387323 hsa-miR-1273f 0.3974819 hsa-miR-6849-5p 0.4550206

Supplementary Table S2: Univariate analysis of clinicopathological characteristics and the five-miRNA-signature with freedom from recurrence (training and validation set) Univariate Cox proportional hazards regression analysis of the endpoint freedom from recurrence in the training (DKTK- ROG) and validation set (LMU-KKG). P-values are derived by log-rank test. p< 0.05 are written in bold.

Training set DKTK-ROG Validation set LMU-KKG (n=85) (n=77) Parameter HR (95% CI) p-value HR (95% CI) p-value Sex (male vs female) 1.01 (0.44-2.34) 0.98 1.62 (0.65-4.04) 0.29 Age at diagnosis (younger than 55 years vs 55 years or older) 1.60 (0.79-3.21) 0.19 1.65 (0.65-4.19) 0.29 Tumor localization (Oral cavity vs Hypopharynx) 1.17 (0.45-3.07) 0.75 0.80 (0.25-2.52) 0.70 (Oropharynx vs Hypopharynx) 0.81 (0.49-1.32) 0.39 0.63 (0.20-1.99) 0.42 (Oropharynx vs Oral cavity) 0.55 (0.25-1.19) 0.12 0.75 (0.26-2.15) 0.60 TNM T stage (T3/T4 vs T1/T2) 2.05 (1.02-4.14) 0.040 3.01 (1.18-7.66) 0.015 TNM N stage (N2/N3 vs N0/N1) 1.97 (0.75-5.19) 0.16 1.28 (0.52-3.16) 0.59 Lymphovascular invasion (yes vs no) 2.43 (1.10-5.36) 0.023 2.89 (1.07-7.81) 0.029 Venous tumor invasion (yes vs no) 1.66 (0.57-4.82) 0.35 0.70 (0.09-5.27) 0.72 Resection margin status (positive vs negative) 1.11 (0.55-2.22) 0.77 0.76 (0.25-2.29) 0.62 Extracapsular extension (yes vs no) 2.21 (1.07-4.56) 0.028 2.18 (0.88-5.37) 0.083 Grading (3 vs 1/2) 0.97 (0.48-1.99) 0.94 1.75 (0.70-4.35) 0.22 Smoking status (smoker vs non-smoker) 1.46 (0.33-6.41) 0.61 0.89 (0.20-4.00) 0.88 Five-miRNA-signature (high-risk vs low-risk) 4.42 (1.98-9.88) <0.001 4.24 (1.40-12.81) 0.005

Supplementary Table S3: Experimentally validated target genes of the five signature miRNAs Experimentally validated miRNA-target interactions stored at miRTarBase. Common target genes (n=12) of the five signature miRNAs are written in bold.

hsa-let-7g-3p hsa-miR-6508-5p hsa-miR-210-5p hsa-miR-4306 hsa-miR-7161-3p (n=88) (n=67) (n=41) (n=187) (n=45) ABI2 SEL1L3 ABHD5 APBB3 ABCC5 GATA6 SLC26A9 AFF4 ACSM2B SKIL ANKRD11 BTG2 ADD2 GDF5OS SLC29A2 ALG14 AGPAT5 SMARCA5 ASS1 CCDC71L AFF2 GFPT1 SLC30A7 AMMECR1L ANP32B SMC3 ATP11A CENPP AGO2 GFRAL SLC31A1 ANTXR2 APP SNRPB BBS9 CHD4 AHCYL2 GLI4 SLC38A1 ARHGEF28 ARID1A STARD8 BCL2L11 COL14A1 ALDH9A1 GPR137C SLITRK5 ATXN2L ARL10 TMEM136 C2orf48 DAZAP2 AMOTL2 GRWD1 SMCR7L BCL2L2-PABPN1 BACH2 TMPRSS12 CCDC169 FAM134C ANKRD45 GXYLT2 SOD2 BCL3 C16orf52 TOP1MT CCDC90B FBXO28 ARHGAP39 HAAO SPATA2 CADM1 C17orf58 TP53INP1 CCNG1 GGA1 ARHGEF6 HACE1 SRCAP CANX CAD TRA2B CD59 GIGYF1 ARID1A HDX SREBF2 COPRS CADM1 UBASH3B CNOT6L GMPR ARID5B HHIP ST6GAL2 DEK CALM2 URM1 DDX3X HIP1 ARIH1 HIST3H2BB STK38 EID1 CCNB1 USMG5 EBAG9 HIST2H2AA3 ATP6AP1 HOXC6 STX6 FAM151B CES3 VEZF1 EIF2S3 HIST2H2AA4 B4GALT1 HSD11B1L SUGT1 FZD6 CITED2 WAC FHL2 HSPE1-MOB4 B4GALT5 IGDCC4 SUOX GTPBP4 CKS2 ZCCHC2 FOXN3 IFNLR1 BACH1 IGFBP5 SYT2 IGF1R DENND5B ZFYVE21 FSIP2 INSIG1 BASP1 IKBKG SYT7 ITGB3BP DLC1 ZMIZ1 GTF2A1 LONRF2 BHLHA15 INCENP TAGLN2 KCNK5 DOCK7 ZNF107 HEPHL1 LRRC20 BNC2 IP6K1 TAOK1 KLHL15 EPHX4 ZNF117 HIST1H2BD MEF2D BTBD3 IQSEC2 TBC1D13 MAT1A FAM127B HPS4 MINOS1 BTBD9 KAT7 TEX261 METTL14 FBXL3 IPMK MOB4 BTG2 KBTBD3 TFDP1 MYH15 FHL2 KANSL1 MRO C10orf105 KHSRP TIGD5 NBEAL1 FKBP14 KLHL15 MSANTD4 C11orf74 KIAA2018 TIGIT NNT FNDC3A KLHL20 NACC2 C15orf43 KIF6 TLE3 NUDT21 FYN KPNA1 NIPAL1 C4orf32 KLF16 TM9SF1 PCCB GABRB3 LANCL3 NOTCH2 C6orf106 LPCAT3 TMEM109 PMEPA1 GNAT1 LHFPL3 PDE7A CADM1 LRP3 TMEM184A POTEG GPR141 LUZP1 PDRG1 CALM3 LY6H TMEM189 POTEM HAT1 MDM2 RBM38 CAPZB MDM2 TMEM189-UBE2V1 RABGAP1L HIST1H1E MED24 REXO2 CASKIN1 METTL22 TMEM214 RPS4Y1 HMGA2 MRPS30 RPL18A CCDC86 MEX3A TMEM86A SDAD1 HMGB2 MTRNR2L10 SCN7A CCDC88A MRAS TMOD3 SLC44A1 HMGXB4 MTRNR2L6 SNX12 CCND2 MRE11A TMPRSS5 SNAP29 IGF1R MTRNR2L8 SPTLC2 CD180 MRPL34 TNRC6A SPIB INCENP NDUFV3 STX17 CDK14 MYBL1 TP53 SQSTM1 JAG2 NT5DC3 USP49 CHRDL1 MYH14 TSPYL4 STYX KAT7 NUP35 XKR4 CHST11 NRG4 TXLNG TBC1D8 KCNB1 NUP50 ZAK CNOT6L OAS2 UBE2V1 TG KLHL15 PCTP ZKSCAN2 CNTNAP2 PABPC1L2A UMPS U2SURP KPNA2 PLA2G2C COCH PABPC1L2B USB1 VPS52 LHFP PPP1R3D CREB3L2 PDE4A VPS39 YOD1 LMNB2 PPP1R3E CSF1 PHLDA2 WDTC1 ZNF175 MAGED1 PSAT1 CSNK1E PKD1 ZADH2 ZNF460 MANBAL RABGEF1 CYP2W1 PKNOX2 ZBTB44 MAP7 RAP2B DCUN1D3 PLAGL2 ZC3H11A MRPS21 RPL24 DLGAP4 POGK ZC3H12B MT2A RPRD2 DLX6 POTED ZFYVE27 MYO10 SAMD9L DNAJC10 POU2F1 ZNF385A NCL SCO1 DPF1 PPAP2B ZNF444 NDUFS1 SEC63 DUSP7 PPP2R1B ZNF561 OLR1 SEH1L EDAR PRELP ZNF606 PCGF3 SMIM18 EFNA1 PRRT2 PIAS1 SOD2 EIF5AL1 PSME3 POU2F1 TAF7 ELAVL3 RAB32 PTP4A1 TEF ELOVL1 RAB40C PTPRF TMBIM6 ENPP5 RAB5B RAB3IP TMEM97 ENTPD7 RANBP10 RAB5C TOB2 EPS15L1 RAPGEF1 RAD23B TRPV2 FAM103A1 RBPJL RAPH1 YPEL1 FAM195B RPP25 RBM23 ZKSCAN8 FAM210A SAMD4B RBM27 ZNF134 FAM228A SBK1 RPS3 ZNF136 FAM53C SCD SCAMP1 ZNF800 FAM83G SHISA9 SCAMP2 ZNFX1 G3BP1 SLC25A28

Supplementary Table S4: Significantly enriched pathways (p-value<0.1) of the mRNA target genes of the five signature miRNAs Common target genes (n=12) of the five signature miRNAs are written in bold.

Matching Pathway Genes [%]* Pre-NOTCH Expression and Processing(R) 15.8 TFDP1, B4GALT1, NOTCH2, TP53, AGO2, TNRC6A CREB3L2, DDX3X, IKBKG, HIST3H2BB, RBPJL, Viral carcinogenesis(K) 4.9 TP53, CCND2, MDM2, CHD4, HIST1H2BD ITGB3BP, INCENP, TAOK1, SEH1L, CENPP, SMC3, Mitotic Prometaphase(R) 7.1 CCNB1 Gene Silencing by RNA(R) 7.6 NUP35, MYBL1, NUP50, SEH1L, AGO2, TNRC6A Oncogene Induced Senescence(R) 13.3 TFDP1, TP53, MDM2, TNRC6A CCNG1, TFDP1, ZNF385A, TP53, BTG2, MDM2, Direct p53 effectors(N) 5.3 CCNB1 Nucleotide-binding domain. leucine rich repeat 10.5 APP, UBE2V1, SUGT1, IKBKG containing receptor (NLR) signaling pathways(R) ISG15 antiviral mechanism(R) 7.5 NUP35, NUP50, SEH1L, KPNA2, KPNA1 p53 signaling pathway(K) 7.4 CCNG1, TP53, CCND2, MDM2, CCNB1 p75(NTR)-mediated signaling(N) 7.2 MAGED1, APP, IKBKG, TP53, SQSTM1 SUMOylation(R) 6.0 INCENP, NUP35, PIAS1, NUP50, SEH1L, SMC3 DNA Double Strand Break Response(R) 9.1 SMARCA5, MRE11A, TP53, KPNA2 Validated targets of C-MYC transcriptional activation(N) 6.7 CAD, TP53, NCL, CCND2, CCNB1 Alzheimer disease-presenilin pathway(P) 5.4 APP, KAT7, NOTCH2, FZD6, APBB3, LRP3 ITGB3BP, INCENP, TAOK1, SEH1L, PSME3, Mitotic Metaphase and Anaphase(R) 4.3 CENPP, SMC3 P53 pathway feedback loops 1(P) 33.3 TP53, MDM2 p53 pathway feedback loops 2(P) 12.5 CCNG1, TP53, MDM2 Metabolism of non-coding RNA(R) 7.8 NUP35, SNRPB, NUP50, SEH1L Cell cycle(K) 4.8 TFDP1, TP53, CCND2, MDM2, SMC3, CCNB1 Prostate cancer(K) 5.6 CREB3L2, IKBKG, TP53, MDM2, IGF1R DNA Damage/Telomere Stress Induced Senescence(R) 11.1 MRE11A, TP53, HMGA2 p53 pathway(N) 7.0 CCNG1, TP53, MDM2, CSNK1E FoxO signaling pathway(K) 4.5 CCND2, MDM2, IGF1R, SOD2, CCNB1, CSNK1E Ribosome(K) 4.4 MRPL34, MRPS21, RPL18A, RPS3, RPS4Y1, RPL24 Nucleosome assembly(R) 10.3 ITGB3BP, SMARCA5, CENPP btg family proteins and cell cycle regulation(B) 22.2 TP53, BTG2 Oxidative Stress Induced Senescence(R) 6.3 TFDP1, TP53, MDM2, TNRC6A Mitotic Prophase(R) 6.1 NUP35, NUP50, SEH1L, CCNB1 IL1-mediated signaling events(N) 8.8 UBE2V1, IKBKG, SQSTM1 ATM pathway(N) 8.8 MRE11A, MDM2, SMC3 Signaling events mediated by TCPTP(N) 8.6 PIAS1, KPNA2, CSF1 p53 signaling pathway(B) 18.2 TP53, MDM2 ITGB3BP, MAGED1, RAPGEF1, ARHGEF6, MDM2, Signalling by NGF(R) 2.6 PSME3, SQSTM1, AGO2, TNRC6A, FYN Eukaryotic Translation Initiation(R) 4.4 EIF2S3, RPL18A, RPS3, RPS4Y1, RPL24 double stranded rna induced gene expression(B) 15.4 IKBKG, TP53 RNA degradation(K) 5.2 CNOT6L, PABPC1L2A, BTG2, TOB2 (B) BioCarta, (K) KEGG Pathway, (N) NCI - Nature Curated Data, (P) pantherdb, (R) Reactome *Percentage of differentially expressed genes of all genes in a pathway