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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  Alignment to reference  Fragmentation by sonication  Image processing Quality Filters  Bioinformatic discovery tools  1  ai  i  (1,2,, I ) Ni Ci  Ci  Ci  {LOSS, NEUT , GAIN , AMP, HLAMP}  Ci {NEUT , GAIN , AMP, HLAMP} c Gi N ic ∈  ai ∈   ck  c  Ci  c  {aa, ab, bb}if c  {LOSS, NEUT }   {aaa, aab, abb, bbb}if c  GAIN  G ic  k ,k   {aaaa, aaab, aabb, abbb, bbbb}if c  AMP  {aaaaa, aaaab, aaabb, aabbb, abbbb, bbbbb}if c  HLAMP  Gic  k  (2.1)  Ci  AMP  {𝑎𝑎𝑎𝑎, 𝑎𝑎𝑎𝑏, 𝑎𝑎𝑏𝑏, 𝑎𝑏𝑏𝑏, 𝑏𝑏𝑏𝑏}  𝜇𝑘𝑐  Gic  k   p(ai | N i , G  k , Ci  c, kc )  Binomial (ai | kc , N i ) c i  (2.2)  ai c  c  𝑝 𝐺𝑖𝑐 = 𝑘 = 𝑀𝑢𝑙𝑡𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝐺𝑖𝑐 = 𝑘|𝜋 𝑐 , 1)  𝑖 ∈ (1,2. . 𝐼𝑐 )   Ic   𝑝  𝐺𝑖𝑐  = 𝑘 𝑎𝑖 , 𝑁𝑖 , 𝐶𝑖 =  𝑐, 𝜇𝑘𝑐 , 𝜋 𝑐  =  𝜋𝑘𝑐 𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙 𝑎𝑖 𝜇𝑘𝑐 , 𝑁𝑖 𝑘𝑐 𝑐 ℎ =1 𝜋ℎ 𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙  𝑎𝑖 𝜇𝑘𝑐 , 𝑁𝑖  (2.3)  𝑘𝑐 p(Gic  k | ai , N i , Ci  c,  kc ,  c )  p( SNVi )   p(Gic  v | ai , N i , Ci  c, vc ,  c ) vV  vV    (2.4)  *  2  c  c c     kc      kc ,  kc   kc ,  kc  α β  Param α α α α β β β β δ δ δ δ  CN State Loss/Neut Gain Amp. HL. Amp Loss/Neut Gain Amp. HL. Amp Loss/Neut Gain Amp. HL. Amp  Values 1000,500,1 1000,500,200,1 1000,350,150,50,1 1000,350,200,100,10,1 1,500,1000 1,200,500,1000 1,50,150,350,1000 1000,350,200,100,10,1 95,4,1 93,4,2,1 90,4,3,2,1 85,5,4,3,2,1    ( 1c:K ,  c ) c  𝑝(𝑆𝑁𝑉𝑖 )    Ic    c  {LOSS / NEUT , GAIN , AMP, HLAMP} p(Gic  k | ai , N i , Ci  c,  kc ,  c )  i  Ic   kc ,  c   kc ,  c  ˆ kc   a  iI c  N  iI c  ˆ kc  I ( Gic  k ) i    kc  1 (2.5)  I ( Gic  k ) i      2 c k  c k   I (G  k )     I (G  j)   iI c  j iI c  c i  c k  c i    (2.6) c j        Genotype  Depth  Frequency of minor allele  Depth  Frequency of minor allele  Depth  Frequency of minor allele  Ref. Allele  Ref. Allele Count  Nref. Allele  Nref. Allele Count  PEF1  1.11 (M)  G  A  17  3  0.8459  aab  11190  0.0441  617  0.0340  27129  0.4731  G  2  N  0  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  Depth  S177L  177905078  Gene Name  31870778  1  AA Mutation  1  Position  p(snv)  Transcriptome  Nref count  METASTATIC VALIDATION  Mut Base  PRIMARY VALIDATION  Ref Base  NORMAL VALIDATION  Functional Impact  Chromosome  WGSS ANALYSIS  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  AA mutation  Gene  Depth  Nref Prop.  Depth  Nref.Prop.  Ref. Allele  Ref. Allele Count  Nref. Allele  Nref. Allele Count  Chi sq. q-value  Transcriptome  Positions  Metastatic  Chromosome  Normal  1  144932587  F218C  AL139152.7  17928  0.3169  18017  0.2164  T  55  G  3  1  149999951  I213V  MRPL9  5387  0.2046  8770  0.0409  T  154  C  28  1  150543396  R3530S  FLG  61790  0.6191  78410  0.3981  N  0  N  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  1.27E102 4.29E211 0  TPR = 1.00 TPR = 0.982  TPR = 0.992 TPR = 0.985    𝜇𝑎𝑎 ≅ 1  𝜇𝑎𝑏 ≅ 0.5  𝜇𝑘  Probability Density  µ α 𝒑(𝝁𝒌 |𝜶, 𝜷)  β α  𝝁𝒌  β  𝜇𝑘  𝜇𝑘  𝜇𝑘  𝑝𝑜𝑠𝑡𝑒𝑟𝑖𝑜𝑟𝑘 ∝ 𝑝𝑟𝑖𝑜𝑟𝑘 × 𝑙𝑖𝑘𝑒𝑙𝑖ℎ𝑜𝑜𝑑𝑘  𝜇𝑘 α 𝐵𝑒𝑡𝑎 𝜇𝑘 𝛼, 𝛽  𝜇𝑘 β : 𝑝 𝜇𝑘 𝛼, 𝛽 = 𝜇𝑘  𝜇𝑘  𝜇𝑘  𝜇𝑘 𝜇𝑘  α  α  β  β  𝛼 → ∞ 𝑎𝑛𝑑 𝛽 → ∞  𝜇𝑘  𝑝 𝜇𝑘 𝑎 𝑇 ) ∝ 𝐵𝑒𝑡𝑎(𝑎1:𝑇 + 𝛼, 𝑏𝑖1:𝑇 + 𝛽) 𝑖 𝑎𝑖  𝑇≫𝛼  𝑏𝑖  𝛼  𝛽  𝜇𝑘 𝜇𝑘  ˆ k   a iT  N  iT  I ( Gi  k ) i  I ( Gi  k ) i  𝜇𝑘  𝑝(𝑎|𝐷)   k 1   k  k  2  (3.1)  𝑝(𝜇𝑘 |𝐷)  𝜇𝑘 𝑝 𝑎 𝐷 = 𝑝(𝑎|𝜇𝑘 )𝑝(𝜇𝑘 |𝐷)  (3.2)  𝜇𝑘 𝜇𝑘 𝑝 𝑎𝐷 =  (3.3)  𝑝 𝑎 𝜇𝑘 𝑝 𝜇𝑘 𝐷 𝑑𝜇𝑘  𝜇𝑘  𝑝 𝑎𝐷 =  𝑝 𝑎 𝜇𝑘 𝑝 𝜇𝑘 𝐷 𝑑𝜇𝑘 =  1 𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑎| 𝜇𝑘 , 𝑁)𝐵𝑒𝑡𝑎 0  =  1 𝑁 0 𝑎  𝜇𝑘 𝛼, 𝛽 𝑑𝜇𝑘  𝛤(𝛼+𝛽 )  𝜇𝑘 𝑎 (1 − 𝜇𝑘 )𝑁−𝑎 × 𝛤  ≝BetaBinom(a|α,β,N) =  𝛼 𝛤(𝛽 )  𝜇𝑘 𝛼 −1 (1 − 𝜇𝑘 )𝛽 −1 𝑑𝜇𝑘  𝐵𝑒𝑡𝑎 (𝑎 +𝛼 ,𝑁−𝑎 + 𝛽 ) 𝑁 𝑎 𝐵𝑒𝑡𝑎 (𝛼 ,𝛽 )  𝜇𝑘  𝜇𝑘  𝜇𝑘  α  𝛽  𝑝(𝜇𝑘 ) 𝜇𝑘  𝑝 𝜇𝑘 = 1  𝑙𝑖𝑘𝑒𝑙𝑖ℎ𝑜𝑜𝑑𝑘  𝑝𝑟𝑖𝑜𝑟𝑘  p(Gi  k | ai , N i ,  )  𝜇𝑘 α  .  β  α  β  α β  𝒂 ∈ [0, 𝑁]  α  β  α α  α  β  β  β 𝜶 = 1000,500,1 α  𝜶 = 10,5,1 𝜶 = 50,5,1  𝜷 = [1,500,1000] β  𝜷 = [1,5,10] 𝜷 = [1,5,10]  𝜏  𝜶 = 100,50,1 𝜏  𝜏, 𝜷 = [1,50,100]  𝜏 𝜏  α  α α  β  β β  α  β  α  β  α  αk ,βk  𝜏  β  𝑒𝑥𝑝 ∈ [0,1,2] α  β  α  β  𝛼𝑘  𝜇𝑘  𝛼 𝑘 +𝛽𝑘  𝜋𝑘  𝜏  𝒂 ∈ [0, 𝑁]  α  β α  β 𝛼=  1000,500,1  𝛽 = [1,500,1000]  𝜏  𝜏 𝛼 = 100,50,1  𝜏  𝛽 = [1,50,100]  𝛼 = 10,5,1 𝛽 = [1,5,10]  𝛼 = 1000,500,1 𝛽 = [1,50,10]  𝛽 = 1,500,1000  𝛼 = 100,50,1  𝛽 = [1,50,100]  𝛼 = 10,50,1  𝛼 = 50,5,1  𝛽 = [1,5,10]  α  β  𝛼 = 50,5,1  𝛽 = [1,5,10]  𝜏  𝜏α  β  [𝟏, 𝟓𝟎𝟎, 𝟏𝟎𝟎𝟎]  𝜶 = 𝟏𝟎𝟎, 𝟓𝟎, 𝟏 𝜶 = 𝟓𝟎, 𝟓, 𝟏  𝜷 = [𝟏, 𝟓𝟎, 𝟏𝟎𝟎] 𝜷 = [𝟏, 𝟓, 𝟏𝟎]  𝜶 = 𝟏𝟎𝟎𝟎, 𝟓𝟎𝟎, 𝟏 𝜷= 𝜶 = 𝟏𝟎, 𝟓, 𝟏 𝜷 = [𝟏, 𝟓, 𝟏]  𝜏  𝜏  𝜏  3  𝜇𝑘  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]  α =[9.0,6.5,3.0]  𝑧 ∈ [7.0,9.9]  β=[1.0,3.5,7.0]  𝜶𝒂𝒂 β  𝜶𝒂𝒂  𝜶𝒂𝒃 𝜶𝒂𝒂  𝜶𝒃𝒃  𝝉  α  α  β  β  𝝉  α  α  β  α= [9.9,6.5,2.5]  β=[0.1,3.5,7.5]  α =[9.0,6.5,3.0]  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  Total # of SNV calls  𝜏 𝜏 𝜏  𝜏 𝜏 𝜏  𝜏 𝜏 𝜏 𝜏  𝜏  𝜏 𝜏  𝜏  Ref  Ref Count  Nref  Nref Count  CN State  P(SNV) Strength 1  P(SNV) Strength 10  P(SNV) Strength 100  P(SNV)  1 1 1 1 2 4 5 5 6 6 6 7 11 14 14 19 19 19 19 19 19 19 19 19  31870778 177905078 181813423 200099346 100965216 25524942 175726007 176953851 44361861 111800869 157570350 139446250 2383399 93999360 100417938 6403457 42881337 45591960 47506592 54648470 57509248 59779115 61757367 63542071  G C C G A C G G C G G G T G C C T C C G G G G G  17 105 68 87 45 9 38 46 24 35 52 37 13 24 19 9 65 33 42 35 51 42 64 66  A T G C T G A T T T A C A A T T A T T T C A C A  3 12 10 9 6 2 6 7 4 6 7 6 3 4 4 2 7 5 5 5 9 6 7 7  3 5 5 5 4 3 4 4 4 3 4 4 4 4 4 3 5 5 5 5 5 5 5 5  0.813 0.402 0.489 0.368 0.275 0.842 0.319 0.313 0.321 0.830 0.280 0.327 0.399 0.321 0.390 0.842 0.377 0.482 0.402 0.462 0.560 0.467 0.382 0.373  0.964 0.919 0.962 0.841 0.858 0.949 0.917 0.936 0.816 0.993 0.899 0.924 0.805 0.816 0.887 0.949 0.801 0.872 0.845 0.984 0.886 0.808 0.795 0.964  0.998 1.000 1.000 0.999 0.996 0.989 0.998 0.999 0.973 1.000 0.999 0.998 0.935 0.973 0.985 0.989 0.997 0.990 0.979 0.987 1.000 0.996 0.997 0.997  1.000 1.000 1.000 1.000 0.999 0.994 0.999 1.000 0.983 1.000 1.000 0.999 0.949 0.983 0.991 0.994 1.000 0.996 0.992 0.995 1.000 0.999 1.000 1.000  𝜏  P(SNV) EM updating  Position  Binomial  Chromosome  Beta-Binomial  0.845 0.999 0.999 0.991 0.853 0.793 0.957 0.978 0.785 0.993 0.935 0.964 0.770 0.785 0.906 0.793 0.954 0.914 0.807 0.894 0.999 0.968 0.958 0.949  𝜇𝑘 𝜇𝑘  α  β 𝜏  𝜏  α  β  BetaBinom(a|α,β,N)  α  β  α  𝐵𝑒𝑡𝑎(𝛼, 𝛽) 𝑁 𝑖𝑓 𝛼, 𝛽 ≫ 𝑁 𝐵𝑒𝑡𝑎(𝛼, 𝛽) 𝑎  𝑁 𝑎  𝜏  α  β 𝐺 = 𝑎𝑎  β  𝜏  α  α  α  𝜇𝑎𝑎  β  ,  β  β  𝜇𝑎𝑏  𝜇𝑎𝑎  𝜏  α  β  α  β  𝜇𝑘  𝜇𝑘 𝜇𝑘 .  α  β           

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