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Mutation discovery in regions of segmental cancer genome amplifications from next generation sequencing… Anamaria, Crisan 2010

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                                   α β               Excision and purification Fragmentation by sonication Image processing Quality Filters Alignment to reference Bioinformatic discovery tools             1    ia ),,2,1( Ii  iN iC iC },,,,{ HLAMPAMPGAINNEUTLOSSCi   cCi  kG c i              HLAMPcifbbbbbabbbbaabbbaaabbaaaabaaaaa AMPcifbbbbabbbaabbaaabaaaa GAINcifbbbabbaabaaa NEUTLOSScifbbabaa kkG ci },,,,,{ },,,,{ },,,{ },{},,{ , (2.1) },,,{ HLAMPAMPGAINNEUTCi G c i N c i ∈ ai ∈  c  c k  AMPCi  {𝑎𝑎𝑎𝑎, 𝑎𝑎𝑎𝑏, 𝑎𝑎𝑏𝑏, 𝑎𝑏𝑏𝑏, 𝑏𝑏𝑏𝑏} 𝜇𝑘 𝑐 ),|(),,,|( i c ki c ki c iii NaBinomialcCkGNap   ia   c 𝑝 𝐺𝑖 𝑐 = 𝑘 = 𝑀𝑢𝑙𝑡𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝐺𝑖 𝑐 = 𝑘|𝜋𝑐 , 1)  𝑖 ∈ (1,2. . 𝐼𝑐) cI 𝑝 𝐺𝑖 𝑐 = 𝑘 𝑎𝑖 , 𝑁𝑖 , 𝐶𝑖 = 𝑐, 𝜇𝑘 𝑐 , 𝜋𝑐 = 𝜋𝑘 𝑐𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙 𝑎𝑖 𝜇𝑘 𝑐 , 𝑁𝑖  𝜋ℎ 𝑐𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙 𝑎𝑖  𝜇𝑘 𝑐 , 𝑁𝑖 𝑘𝑐 ℎ=1  𝑘𝑐 ),,,,|( cckiii c i cCNakGp     Vv cc viii c ii cCNavGpSNVp ),,,,|()(   Gi c k   c  vV (2.2) (2.3) (2.4)  *  c k c k c k  , c k c k  , α β   c   c   c   2  (2.6) Param CN State Values α Loss/Neut 1000,500,1 α Gain 1000,500,200,1 α Amp. 1000,350,150,50,1 α HL. Amp 1000,350,200,100,10,1 β Loss/Neut 1,500,1000 β Gain 1,200,500,1000 β Amp. 1,50,150,350,1000 β HL. Amp 1000,350,200,100,10,1 δ Loss/Neut 95,4,1 δ Gain 93,4,2,1 δ Amp. 90,4,3,2,1 δ HL. Amp 85,5,4,3,2,1 ),( :1 cc Kc   𝑝(𝑆𝑁𝑉𝑖) cI },,,/{ HLAMPAMPGAINNEUTLOSSc ),,,,|( cckiii c i cCNakGp  cIi cc k  , cc k  ,          c c i c c i Ii c k c k kGI i Ii c k kGI i c k N a 2 1 ˆ )( )(           j Ii c j c i Ii c k c i c k c c jGI kGI    )( )( ˆ    (2.5)               WGSS ANALYSIS NORMAL VALIDATION PRIMARY VALIDATION METASTATIC VALIDATION Transcriptome  C h ro m o s o m e  P o s it io n  A A  M u ta ti o n  G e n e  N a m e  F u n c ti o n a l I m p a c t  R e f B a s e  M u t B a s e  D e p th  N re f c o u n t  p ( s n v )  G e n o ty p e  D e p th  F re q u e n c y  o f m in o r a ll e le  D e p th  F re q u e n c y  o f m in o r a ll e le  D e p th  F re q u e n c y  o f m in o r a ll e le  R e f.  A ll e le  R e f.  A ll e le  C o u n t N re f.  A ll e le  N re f.  A ll e le  C o u n t  1 31870778 S177L PEF1 1.11 (M) G A 17 3 0.8459 aab 11190 0.0441 617 0.0340 27129 0.4731 G 2 N 0 1 177905078 Q872* TDRD5 Truncating C T 105 12 0.9999 aaaab 38705 0.0022 2474 0.0020 59250 0.0953 C 18 N 0 1 181813423 Q100H NCF2 0.975 (L) C G 68 10 0.9998 aaaab 39290 0.0039 1733 0.0069 60040 0.0977 C 25 N 0 1 200099346 R539T IPO9 2.025 (H) G C 87 9 0.9913 aaaab 18800 0.0026 274 0.0036 12231 0.0916 G 84 C 11 2 100965216 E525T NPAS2 1.68 (M) A T 45 6 0.8536 aaab 131465 0.0017 15627 0.0022 187617 0.1796 A 29 T 3 4 25524942 S->C AC133961.3 No Uni ID. C G 9 2 0.7930 aab 10999 0.0025 443 0.0045 15554 0.2468 N 0 N 0 5 175726007 E68K ARL10 0.55 (L) G A 38 6 0.9575 aaab 35722 0.0011 5911 0.0008 56243 0.1454 G 1 N 0 5 176953851 E152* TMED9 Truncating G T 46 7 0.9787 aaab 83887 0.0110 40283 0.0109 97795 0.2028 G 111 T 9 6 44361861 E222K TCTE1 0.955 (L) C T 24 4 0.7858 aaab 63261 0.0054 4076 0.0064 70470 0.2327 N 0 N 0 6 111800869 N1794K REV3L 0.345 (L) G T 35 6 0.9933 aab 91581 0.0016 54683 0.0020 74407 0.2006 G 18 T 3 6 157570350 R2115Q ARID1B 1.845 (M) G A 52 7 0.9353 aaab 304781 0.0024 118051 0.0022 449145 0.2051 N 0 N 0 7 139446250 L561V JHDM1D 0.615 (L) G C 37 6 0.9647 aaab 305 0.0000 1 0.0000 137 0.2774 G 91 C 30 11 2383399 I109F TRPM5 -0.08 (N) T A 13 3 0.7705 aaab 100659 0.0045 33904 0.0104 182328 0.1948 N 0 N 0 14 93999360 V359V SERPINA9 0.28(L) G A 24 4 0.7858 aaab 61006 0.0219 8291 0.0226 73354 0.2324 N 0 N 0 14 100417938 V982I RTL1 0805 (L) C T 19 4 0.9063 aaab 107685 0.0135 6172 0.0146 102285 0.1799 N 0 N 0 19 6403457 G313S SLC25A23 1.83 (M) C T 9 2 0.7930 aab 46019 0.0048 6579 0.0050 43855 0.2087 C 1 T 2 19 42881337 K187M ZNF607 NA T A 65 7 0.9540 aaaab 2722 0.0026 174 0.1667 13589 0.1525 T 15 A 1 19 45591960 R1380H PRX 0.55 (L) C T 33 5 0.9146 aaaab 14090 0.0076 35487 0.0063 41892 0.1068 N 0 N 0 19 47506592 E24* PRR19 Truncating C T 42 5 0.8074 aaaab 47838 0.0018 2712 0.0026 53450 0.1260 C 5 N 0 19 54648470 Q311* ALDH16A1 Truncating G T 35 5 0.8964 aaaab 75066 0.0036 1935 0.0078 91868 0.1159 N 0 N 0 19 57509248 E16Q ZNF480 1.67 (M) G C 51 9 0.9998 aaaab 16867 0.0033 1133 0.0071 52154 0.0862 G 12 C 1 19 59779115 V328M LILRA2 1.91 (M) G A 42 6 0.9682 aaaab 145106 0.0029 60245 0.0028 264119 0.1177 G 6 N 0 19 61757367 Q467H ZFP28 0.805 (L) G C 64 7 0.9583 aaaab 279 0.0036 7 0.1429 393 0.1018 G 4 C 2 19 63542071 G348E ZSCAN22 2.99 (H) G A 66 7 0.9493 aaaab 279784 0.0023 64866 0.0021 218744 0.0996 G 1 N 0    Normal Metastatic Transcriptome  C h ro m o s o m e  P o s it io n s  A A  m u ta ti o n  G e n e  D e p th  N re f P ro p . D e p th  N re f. P ro p . R e f.  A ll e le  R e f.  A ll e le  C o u n t N re f.  A ll e le  N re f.  A ll e le  C o u n t C h i s q . q - v a lu e  1 144932587 F218C AL139152.7 17928 0.3169 18017 0.2164 T 55 G 3 1.27E- 102 1 149999951 I213V MRPL9 5387 0.2046 8770 0.0409 T 154 C 28 4.29E- 211 1 150543396 R3530S FLG 61790 0.6191 78410 0.3981 N 0 N 0 0 8 146033676 A76V ZNF7 92012 0.4499 147007 0.2683 C 2 N 0 0 9 33375641 C->F AQP7 24722 0.2781 22104 0.1985 N 0 N 0 1.12E-89 10 29823914 M1259T SVIL 128591 0.3867 110884 0.4808 A 6 N 0 0 11 390124 N477K PKP3 37172 0.4601 57560 0.2907 C 11 N 0 0 11 17499485 R357Q USH1C 101208 0.5595 58749 0.1548 N 0 N 0 0 11 65860057 A79T RIN1 75400 0.4044 97848 0.1738 N 0 N 0 0 11 116569101 R710C SIDT2 260320 0.5342 237372 0.1390 C 51 T 19 0 11 124827464 E358Q FEZ1 249388 0.5259 171924 0.1372 C 0 G 2 0 12 122455439 R279P STED8 208542 0.3071 175257 0.4182 G 17 N 0 0 17 36549887 S->P KRTAP4-15 1774 0.3207 4409 0.1851 N 0 N 0 1.51E-30 19 40691038 R->Q DMKN 209119 0.5478 247223 0.1696 C 5 T 2 0 19 42074256 H426R ZNF829 6402 0.4531 10867 0.1214 T 1 C 1 0 19 50869860 R190Q GIPR 70793 0.4878 90262 0.1843 G 26 A 5 0 19 59415177 R->K LILRB3 34753 0.1592 46500 0.0642 N 0 N 0 0  TPR = 1.00 TPR = 0.982 TPR = 0.992 TPR = 0.985            𝜇𝑎𝑎 ≅ 1 𝜇𝑎𝑏 ≅ 0.5 𝜇𝑘  𝜇𝑘 𝜇𝑘 𝜇𝑘 𝑝𝑜𝑠𝑡𝑒𝑟𝑖𝑜𝑟𝑘  ∝ 𝑝𝑟𝑖𝑜𝑟𝑘  × 𝑙𝑖𝑘𝑒𝑙𝑖ℎ𝑜𝑜𝑑𝑘 𝜇𝑘 𝜇𝑘 α β : 𝑝 𝜇𝑘  𝛼, 𝛽 =  𝐵𝑒𝑡𝑎 𝜇𝑘  𝛼, 𝛽  𝜇𝑘 𝜇𝑘 𝜇𝑘 α β 𝒑(𝝁𝒌|𝜶, 𝜷) 𝝁𝒌 α β µ P ro b ab il it y  D en si ty   𝜇𝑘 𝜇𝑘 α β α β  𝛼 → ∞ 𝑎𝑛𝑑 𝛽 → ∞ 𝜇𝑘  𝑝 𝜇𝑘 𝑎𝑇) ∝ 𝐵𝑒𝑡𝑎(𝑎𝑖 1:𝑇 + 𝛼, 𝑏𝑖 1:𝑇 + 𝛽) 𝑎𝑖 𝑏𝑖 𝑇 ≫ 𝛼 𝛼 𝛽 𝜇𝑘 𝜇𝑘          Ti kk kGI i Ti k kGI i k i i N a 2 1 ˆ )( )(    𝜇 𝑘 𝑝(𝜇 𝑘|𝐷) 𝑝(𝑎|𝐷) 𝜇 𝑘 𝑝 𝑎 𝐷 =  𝑝(𝑎|𝜇 𝑘)𝑝(𝜇 𝑘|𝐷) (3.1) (3.2)  𝜇𝑘 𝜇 𝑘 𝑝 𝑎 𝐷 =   𝑝 𝑎 𝜇𝑘 𝑝 𝜇𝑘  𝐷 𝑑𝜇𝑘 𝜇𝑘 𝑝 𝑎 𝐷 =   𝑝 𝑎 𝜇 𝑘 𝑝 𝜇 𝑘 𝐷 𝑑𝜇 𝑘 =   𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑎| 1 0 𝜇 𝑘 , 𝑁)𝐵𝑒𝑡𝑎 𝜇 𝑘  𝛼, 𝛽 𝑑𝜇 𝑘 =   𝑁𝑎 𝜇 𝑘 𝑎(1 − 𝜇 𝑘) 𝑁−𝑎 × 𝛤(𝛼+𝛽) 𝛤 𝛼 𝛤(𝛽) 𝜇 𝑘 𝛼−1(1 − 𝜇 𝑘) 𝛽−1𝑑𝜇 𝑘 1 0 ≝BetaBinom(a|α,β,N) = 𝐵𝑒𝑡𝑎 (𝑎+𝛼 ,𝑁−𝑎+ 𝛽 ) 𝐵𝑒𝑡𝑎 (𝛼 ,𝛽)  𝑁 𝑎   𝜇 𝑘 𝜇𝑘 𝜇𝑘 α 𝛽 𝑝(𝜇𝑘) 𝜇𝑘 𝑝 𝜇𝑘 = 1 (3.3)  𝑙𝑖𝑘𝑒𝑙𝑖ℎ𝑜𝑜𝑑𝑘 𝑝𝑟𝑖𝑜𝑟𝑘 ),,|( iii NakGp  𝜇𝑘 α β . α β   α β 𝒂 ∈ [0, 𝑁] α β α β α β α β 𝜶 =  1000,500,1 𝜷 = [1,500,1000] 𝜏 𝜏, α β 𝜶 =  100,50,1 𝜷 = [1,50,100] 𝜏 𝜶 =  10,5,1 𝜷 = [1,5,10] 𝜏 𝜏 𝜶 =  50,5,1 𝜷 = [1,5,10]  α β α β α β α β α β α β 𝜏 αk ,βk 𝑒𝑥𝑝 ∈ [0,1,2] α β 𝜇𝑘 𝛼𝑘 𝛼𝑘+𝛽𝑘 𝜋𝑘 α β  𝜏 𝒂 ∈ [0, 𝑁] α β α β 𝛼 =  1000,500,1 𝛽 = [1,500,1000]  𝜏 𝜏 𝛼 =  100,50,1 𝛽 = [1,50,100] 𝜏 𝛼 =  10,5,1 𝛽 = [1,5,10]  𝛼 =  1000,500,1 𝛽 =  1,500,1000 𝛼 =  100,50,1 𝛽 = [1,50,100] 𝛼 =  10,50,1 𝛽 = [1,50,10]  α β 𝛼 =  50,5,1 𝛽 = [1,5,10] 𝜏 𝜏 α β 𝛼 =  50,5,1 𝛽 = [1,5,10]   𝜏  𝜏  𝜏  3  𝜇𝑘 𝜶 =  𝟏𝟎𝟎𝟎, 𝟓𝟎𝟎, 𝟏 𝜷 = [𝟏, 𝟓𝟎𝟎, 𝟏𝟎𝟎𝟎] 𝜶 =  𝟏𝟎𝟎, 𝟓𝟎, 𝟏 𝜷 = [𝟏, 𝟓𝟎, 𝟏𝟎𝟎] 𝜶 =  𝟏𝟎, 𝟓, 𝟏 𝜷 = [𝟏, 𝟓, 𝟏] 𝜶 =  𝟓𝟎, 𝟓, 𝟏 𝜷 = [𝟏, 𝟓, 𝟏𝟎]  α β α β 𝜏 α β 𝜏 𝜏 α = [9.9,y,z] β=[0.1,w,x], 𝑦 ∈ [4.5,5.5], 𝑤 ∈ [5.5,4.5]  𝑥 ∈ [0.1,3.0], 𝑧 ∈ [7.0,9.9] 𝜇𝑘 α β α = [9.9,6.5,z] β=[0.1,3.5,x] 𝑥 ∈ [0.1,3.0] 𝑧 ∈ [7.0,9.9] α =[9.0,6.5,3.0] β=[1.0,3.5,7.0]  𝜶𝒂𝒂 𝜶𝒂𝒃 𝜶𝒃𝒃 β 𝜶𝒂𝒂 𝜶𝒂𝒂  𝝉  α β α β α = [9.9,6.5,2.5] β=[0.1,3.5,7.5] α =[9.0,6.5,3.0] α α β 𝝉  β=[1.0,3.5,7.0] 𝜏 𝜏 𝝉 𝜏 𝜏 𝝉 𝜇𝑎𝑎 = 0.7445, 𝜇𝑎𝑏 = 0.0018,𝑎𝑛𝑑 𝜇𝑏𝑏 = 0.0001  𝝉 𝝉 𝝉 𝝉 𝝉 𝝉 𝝉 T o ta l #  o f S N V  c al ls   𝜏 𝜏 𝜏 𝜏  𝜏 𝜏 𝜏 𝜏 𝜏 𝜏 𝜏 𝜏 𝜏      Beta-Binomial Binomial C h ro m o so m e P o si ti o n  R ef  R ef  C o u n t N re f N re f C o u n t C N  S ta te  P (S N V ) S tr en g th  1  P (S N V ) S tr en g th  1 0  P (S N V ) S tr en g th  1 0 0  P (S N V ) P (S N V )  E M  u p d a ti n g  1 31870778 G 17 A 3 3 0.813 0.964 0.998 1.000 0.845 1 177905078 C 105 T 12 5 0.402 0.919 1.000 1.000 0.999 1 181813423 C 68 G 10 5 0.489 0.962 1.000 1.000 0.999 1 200099346 G 87 C 9 5 0.368 0.841 0.999 1.000 0.991 2 100965216 A 45 T 6 4 0.275 0.858 0.996 0.999 0.853 4 25524942 C 9 G 2 3 0.842 0.949 0.989 0.994 0.793 5 175726007 G 38 A 6 4 0.319 0.917 0.998 0.999 0.957 5 176953851 G 46 T 7 4 0.313 0.936 0.999 1.000 0.978 6 44361861 C 24 T 4 4 0.321 0.816 0.973 0.983 0.785 6 111800869 G 35 T 6 3 0.830 0.993 1.000 1.000 0.993 6 157570350 G 52 A 7 4 0.280 0.899 0.999 1.000 0.935 7 139446250 G 37 C 6 4 0.327 0.924 0.998 0.999 0.964 11 2383399 T 13 A 3 4 0.399 0.805 0.935 0.949 0.770 14 93999360 G 24 A 4 4 0.321 0.816 0.973 0.983 0.785 14 100417938 C 19 T 4 4 0.390 0.887 0.985 0.991 0.906 19 6403457 C 9 T 2 3 0.842 0.949 0.989 0.994 0.793 19 42881337 T 65 A 7 5 0.377 0.801 0.997 1.000 0.954 19 45591960 C 33 T 5 5 0.482 0.872 0.990 0.996 0.914 19 47506592 C 42 T 5 5 0.402 0.845 0.979 0.992 0.807 19 54648470 G 35 T 5 5 0.462 0.984 0.987 0.995 0.894 19 57509248 G 51 C 9 5 0.560 0.886 1.000 1.000 0.999 19 59779115 G 42 A 6 5 0.467 0.808 0.996 0.999 0.968 19 61757367 G 64 C 7 5 0.382 0.795 0.997 1.000 0.958 19 63542071 G 66 A 7 5 0.373 0.964 0.997 1.000 0.949 𝜏 𝜏  𝜇𝑘 𝜇𝑘 α β 𝜏 𝜏 α β α β                          BetaBinom(a|α,β,N) 𝐵𝑒𝑡𝑎(𝛼, 𝛽) 𝐵𝑒𝑡𝑎(𝛼, 𝛽)  𝑁 𝑎   𝑖𝑓 𝛼, 𝛽 ≫ 𝑁 α β  𝑁 𝑎  𝜏 α β 𝐺 = 𝑎𝑎  𝜏 α β α β α β 𝜇𝑎𝑎  ,  𝜇𝑎𝑏 𝜇𝑎𝑎 𝜏 α β  α β          𝜇𝑘 𝜇𝑘 𝜇𝑘 . α β                     

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