Whole Exome Sequencing of Multi-Regional Biopsies from Metastatic Lesions to Evaluate Actionable Truncal Mutations Using a Single-Pass Percutaneous Technique
Abstract
:1. Introduction
2. Results
2.1. Tumour Variant Load
2.2. Intratumor Heterogeneity
2.3. Statistical Saturation Analysis
2.4. Prediction of Truncal Mutations
2.5. Clinical Therapeutic Intervention
3. Discussion
4. Materials and Methods
4.1. Patients and Specimens Collection
4.2. Whole-Exome Sequencing
4.3. Sequencing Reads Alignment and Somatic Variant Detection
4.4. Copy Number Alterations
4.5. Cancer Gene Panels
4.6. Construction of Phylogenetic Trees
4.7. Statistical Saturation Analysis
4.8. Cancer Cell Fraction and Allele Frequency
4.9. Prediction of Truncal Mutations
4.10. Assessing Targeted Therapy Outcomes
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Appendix A
Sample | Patient | Patient label | Disease | ABSOLUTE_call Status (Called = Clonal) | ABSOLUTE_purity | ABSOLUTE_ploidy | ABSOLUTECancer DNA Faction | ABSOLUTECoverage for 80% Power | VAF Range-All Variants | VAF Range-Putative Truncal Variants | VAF Range-Private Variants | VAF Range-Branch Variants | Mclust.wCN.Cluster# | Mclust.noCN.Cluster# | VAF_ROC_AUC_TruncalVsNonTruncal | VAF_YoudenThreshold_TruncalVsNonTruncal | VAF_YoudenThreshold_TruncalVsNonTruncal_Accuracy | Mclust.cn.threshold_clusterWHighestVAF | Mclust.cn.threshold_TruncalVsNonTruncal_Accuracy | Remark |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
RE3F1 | RE3 | P01 | CRC | called | 0.25 | 5.86 | 0.49 | 64 | 0.14038 | NaN | 0.135531915 | 0.2446 | 2 | 2 | NaN | NaN | NaN | 0.241285714 | NaN | No Truncal Mutation detected |
RE3F2 | RE3 | P01 | CRC | called | 0.21 | 1.94 | 0.2 | 52 | 0.134576087 | NaN | 0.099253968 | 0.152966942 | 1 | 2 | NaN | NaN | NaN | 0.1086 | NaN | No Truncal Mutation detected |
RE3F3 | RE3 | P01 | CRC | called | 0.28 | 4.02 | 0.44 | 49 | 0.146770833 | NaN | 0.143824176 | 0.2004 | 2 | 2 | NaN | NaN | NaN | 0.348666667 | NaN | No Truncal Mutation detected |
RE3F4 | RE3 | P01 | CRC | high non-clonal | 1 | 2.06 | 1 | 8 | 0.383224409 | NaN | 0.30389313 | 0.467715447 | 2 | 2 | NaN | NaN | NaN | 0.447333333 | NaN | No Truncal Mutation detected |
RE4F1 | RE4 | P02 | LUNG | called | 0.39 | 3.83 | 0.55 | 36 | 0.183591928 | 0.191490909 | 0.163944444 | 0.1565 | 2 | 2 | 0.675130617 | 0.076 | 62.27795193 | 0.419666667 | 50.49111808 | --- |
RE4F2 | RE4 | P02 | LUNG | called | 0.5 | 3.81 | 0.65 | 29 | 0.205012195 | 0.226848485 | 0.145166667 | 0.177076923 | 2 | 2 | 0.688477366 | 0.091 | 68.24915825 | 0.2135 | 57.35129068 | --- |
RE4F3 | RE4 | P02 | LUNG | called | 0.22 | 5.43 | 0.43 | 68 | 0.176941909 | 0.192266667 | 0.123045455 | 0.17203125 | 1 | 3 | 0.680582137 | 0.089 | 68.12599681 | 0.20575 | 55.2830941 | --- |
RE4F4 | RE4 | P02 | LUNG | called | 0.42 | 3.85 | 0.58 | 34 | 0.180034043 | 0.194939394 | 0.1438125 | 0.145815789 | 2 | 2 | 0.714545455 | 0.096 | 67.70562771 | 0.5995 | 49.89177489 | --- |
RE6F1 | RE6 | P03 | LUNG | called | 0.2 | 4.03 | 0.33 | 66 | 0.106431818 | 0.156 | 0.085482759 | 0.1505 | 0 | 2 | 0.659375 | 0.364 | 50 | 0.173 | 68.75 | Only 2 Truncal Mutations detected |
RE6F2 | RE6 | P03 | LUNG | called | 0.16 | 1.96 | 0.16 | 66 | 0.106794118 | 0.12125 | 0.102037037 | 0.130333333 | 0 | 3 | 0.575 | 0.5 | 50 | 0.1345 | 63.33333333 | Only 2 Truncal Mutations detected |
RE6F3 | RE6 | P03 | LUNG | called | 0.23 | 2.12 | 0.24 | 47 | 0.105585366 | 0.236 | 0.0839 | 0.124 | 0 | 2 | 0.692567568 | 0.524 | 62.5 | 0.327333333 | 73.64864865 | Only 2 Truncal Mutations detected |
RE6F4 | RE6 | P03 | LUNG | called | 0.16 | 1.07 | 0.09 | 61 | 0.106481481 | 0.21825 | 0.079666667 | 0.191375 | 1 | 2 | 0.7525 | 0.52 | 50 | 0.072 | 60.5 | Only 2 Truncal Mutations detected |
RE8F1 | RE8 | P04 | LUNG | called | 0.32 | 4.21 | 0.49 | 46 | 0.222009821 | 0.225307027 | 0.210836364 | 0.204115108 | 2 | 3 | 0.589563247 | 0.052 | 50.40747256 | 0.296918919 | 53.80586048 | --- |
RE8F2 | RE8 | P04 | LUNG | high non-clonal | 0.58 | 4.34 | 0.75 | 28 | 0.29151633 | 0.316179459 | 0.201833333 | 0.234288194 | 2 | 3 | 0.655537557 | 0.084 | 55.15448764 | 0.565733333 | 54.26535877 | --- |
RE8F3 | RE8 | P04 | LUNG | high entropy | 0.46 | 4.39 | 0.65 | 35 | 0.255151779 | 0.275265946 | 0.156716418 | 0.210709559 | 2 | 3 | 0.658003466 | 0.083 | 53.60034914 | 0.359983051 | 57.10528998 | --- |
RE8F4 | RE8 | P04 | LUNG | called | 0.27 | 3.33 | 0.38 | 47 | 0.192184165 | 0.198313514 | 0.113677419 | 0.187166667 | 3 | 4 | 0.619140554 | 0.049 | 50.58159754 | 0.332363636 | 51.06664348 | --- |
RE9F1 | RE9 | P05 | LUNG | called | 0.22 | 3.87 | 0.36 | 58 | 0.152 | 0.408 | 0.117938776 | 0.157363095 | 1 | 3 | NaN | NaN | NaN | 0.117214286 | NaN | No Truncal Mutation detected |
RE9F2 | RE9 | P05 | LUNG | called | 0.31 | 5.63 | 0.56 | 55 | 0.229921642 | 0.414333333 | 0.141388235 | 0.268655556 | 2 | 3 | NaN | NaN | NaN | 0.416 | NaN | No Truncal Mutation detected |
RE9F3 | RE9 | P05 | LUNG | called | 0.25 | 3.94 | 0.4 | 53 | 0.12454386 | 0.407 | 0.111265306 | 0.0852 | 2 | 2 | NaN | NaN | NaN | 0.08 | NaN | No Truncal Mutation detected |
RE9F4 | RE9 | P05 | LUNG | called | 0.3 | 4.85 | 0.51 | 51 | 0.156137339 | 0.408333333 | 0.112022222 | 0.162778378 | 1 | 2 | NaN | NaN | NaN | 0.1255 | NaN | No Truncal Mutation detected |
RE10F1 | RE10 | P06 | LUNG | called | 0.35 | 6.42 | 0.63 | 55 | 0.233589474 | 0.420242424 | 0.106076923 | 0.2807 | 2 | 4 | 0.9335 | 0.2235 | 89.71 | 0.4315 | 71.11 | --- |
RE10F2 | RE10 | P06 | LUNG | called | 0.24 | 3.98 | 0.38 | 56 | 0.154539216 | 0.229878788 | 0.117761905 | 0.126333333 | 2 | 2 | 0.8304787 | 0.167 | 80.57 | 0.193142857 | 72.99 | --- |
RE10F3 | RE10 | P06 | LUNG | called | 0.26 | 5.3 | 0.48 | 60 | 0.203761905 | 0.402121212 | 0.103064516 | 0.1735 | 2 | 2 | 0.962121212 | 0.311 | 88.13131313 | 0.336714286 | 82.07070707 | --- |
RE10F4 | RE10 | P06 | LUNG | called | 0.35 | 4.34 | 0.54 | 43 | 0.203847826 | 0.376272727 | 0.08216 | 0.247666667 | 2 | 2 | 0.942218798 | 0.273 | 91.88495121 | 0.332857143 | 76.91319979 | --- |
RE5F1 | RE5 | P07 | OV | non-aneuploid | NaN | NaN | NaN | NaN | 0.341515366 | 0.456792381 | 0.119782946 | 0.288920635 | 4 | 3 | 0.953009939 | 0.278 | 93.77748109 | 0.547 | 55.3600356 | --- |
RE5F2 | RE5 | P07 | OV | non-aneuploid | NaN | NaN | NaN | NaN | 0.351859281 | 0.385497143 | 0.176089109 | 0.354071429 | 2 | 3 | 0.767505828 | 0.188 | 76.35164835 | 0.364184211 | 67.12687313 | --- |
RE5F3 | RE5 | P07 | OV | non-aneuploid | NaN | NaN | NaN | NaN | 0.372459689 | 0.42759619 | 0.138438095 | 0.315649351 | 1 | 3 | 0.858644689 | 0.258 | 82.34065934 | 0.378807692 | 79.35531136 | --- |
RE5F4 | RE5 | P07 | OV | non-aneuploid | NaN | NaN | NaN | NaN | 0.391212257 | 0.431544762 | 0.17428125 | 0.3839375 | 2 | 6 | 0.81843254 | 0.28 | 78.18055556 | 0.424096774 | 68.52380952 | --- |
RE11F1 | RE11 | P08 | OV | called | 0.27 | 3.6 | 0.4 | 48 | 0.182677632 | 0.214707071 | 0.109380952 | 0.174272727 | 2 | 3 | 0.825995807 | 0.093 | 80.05526968 | 0.458 | 53.09700781 | --- |
RE11F2 | RE11 | P08 | OV | called | 0.25 | 3.02 | 0.34 | 48 | 0.22096988 | 0.273212121 | 0.119104167 | 0.206105263 | 4 | 3 | 0.80830695 | 0.122 | 79.05924921 | 0.383 | 57.59837178 | --- |
RE11F3 | RE11 | P08 | OV | called | 0.25 | 5.06 | 0.46 | 59 | 0.219164894 | 0.279626263 | 0.135373134 | 0.202272727 | 1 | 3 | 0.806037907 | 0.123 | 79.04891613 | 0.15175 | 77.1422086 | --- |
RE11F4 | RE11 | P08 | OV | called | 0.22 | 4.74 | 0.4 | 65 | 0.225337079 | 0.294050505 | 0.1038 | 0.220416667 | 1 | 3 | 0.837424882 | 0.152 | 80.39253292 | 0.2655 | 67.40825981 | --- |
RE13F1 | RE13 | P09 | OV | called | 0.47 | 5.47 | 0.71 | 41 | 0.196666667 | 0.242578125 | 0.126136364 | 0.215 | 2 | 2 | 0.783166274 | 0.138 | 78.19870283 | 0.370333333 | 55.76356132 | --- |
RE13F2 | RE13 | P09 | OV | called | 0.32 | 5.19 | 0.55 | 50 | 0.254631944 | 0.317359375 | 0.103151515 | 0.275574468 | 1 | 3 | 0.741113281 | 0.229 | 71.875 | 0.259411765 | 66.40625 | --- |
RE13F3 | RE13 | P09 | OV | called | 0.31 | 5.3 | 0.55 | 52 | 0.267333333 | 0.34478125 | 0.112880952 | 0.299893617 | 1 | 3 | 0.738851826 | 0.172 | 72.05933989 | 0.222090909 | 64.9315309 | --- |
RE13F4 | RE13 | P09 | OV | called | 0.33 | 5.21 | 0.57 | 49 | 0.295875969 | 0.355515625 | 0.172761905 | 0.267886364 | 1 | 2 | 0.705288462 | 0.145 | 69.19471154 | 0.229583333 | 64.42307692 | --- |
RE7F1 | RE7 | P10 | BRCA | called | 0.82 | 2.3 | 0.84 | 11 | 0.31790099 | 0.44826087 | 0.1773125 | 0.425285714 | 1 | 2 | 0.832806324 | 0.289 | 82.74703557 | 0.325 | 79.48616601 | --- |
RE7F2 | RE7 | P10 | BRCA | called | 0.78 | 2.32 | 0.81 | 12 | 0.3082 | 0.423347826 | 0.131810811 | 0.483857143 | 1 | 2 | 0.863142292 | 0.304 | 86.56126482 | 0.2225 | 83.05335968 | --- |
RE7F3 | RE7 | P10 | BRCA | called | 0.29 | 5.98 | 0.55 | 59 | 0.311932584 | 0.433630435 | 0.11159375 | 0.385818182 | 1 | 2 | 0.861223458 | 0.3 | 89.76238625 | 0.269 | 86.27401416 | --- |
RE7F4 | RE7 | P10 | BRCA | called | 0.22 | 3.61 | 0.33 | 59 | 0.19171134 | 0.237978261 | 0.143681818 | 0.189571429 | 1 | 2 | 0.805626598 | 0.132 | 83.01364024 | 0.113666667 | 81.15942029 | --- |
RE12F1 | RE12 | P11 | UCEC | high non-clonal | 0.63 | 2.24 | 0.66 | 14 | 0.221503448 | * 0.323226666666667 | 0.112514286 | NaN | 2 | 2 | 0.903142857 | 0.164 | 88.28571429 | 0.31075 | 73.85714286 | --- |
RE12F4 | RE12 | P11 | UCEC | called | 0.66 | 4.45 | 0.81 | 26 | 0.267685185 | * 0.4072 | 0.14737931 | NaN | 3 | 3 | 0.863984674 | 0.194 | 82.59770115 | 0.9165 | 52.09195402 | --- |
RE14F1 | RE14 | P12 | UCEC | called | 0.2 | 4.62 | 0.37 | 68 | 0.217402299 | 0.27652 | 0.110096774 | 0.279166667 | 4 | 3 | 0.885135135 | 0.121 | 86.83783784 | 0.518 | 52.2972973 | --- |
RE14F2 | RE14 | P12 | UCEC | called | 0.26 | 5.79 | 0.51 | 62 | 0.254321839 | 0.30418 | 0.1312 | 0.303083333 | 2 | 3 | 0.817567568 | 0.178 | 82.83783784 | 0.5225 | 51.94594595 | --- |
RE14F3 | RE14 | P12 | UCEC | called | 0.23 | 4.9 | 0.43 | 62 | 0.295 | 0.4168 | 0.101848485 | 0.3215 | 1 | 3 | 0.882173913 | 0.174 | 85.04347826 | 0.4595 | 60.65217391 | --- |
RE14F4 | RE14 | P12 | UCEC | called | 0.22 | 5.48 | 0.44 | 68 | 0.295521277 | 0.423 | 0.110857143 | 0.305444444 | 1 | 3 | 0.888636364 | 0.197 | 88.90909091 | 0.495 | 63.72727273 | --- |
RE15F1 | RE15 | P13 | LIHC | called | 0.43 | 4.05 | 0.61 | 35 | 0.266176 | 0.35 | 0.225596774 | 0.304672131 | 1 | 3 | 0.62601626 | 0.75 | 50 | 0.2527 | 46.54471545 | Only 1 Truncal Mutation detected |
RE15F2 | RE15 | P13 | LIHC | called | 0.23 | 1.96 | 0.23 | 46 | 0.179296296 | 0.2475 | 0.176842105 | 0.164333333 | 0 | 4 | 0.72 | 0.667 | 50 | 0.428666667 | 73 | Only 1 Truncal Mutation detected |
RE15F3 | RE15 | P13 | LIHC | called | 0.23 | 2.04 | 0.23 | 47 | 0.166075949 | 0.3635 | 0.15 | 0.163171875 | 0 | 0 | 0.948051948 | 1 | 50 | NaN | NaN | Only 1 Truncal Mutation detected |
RE15F4 | RE15 | P13 | LIHC | called | 0.2 | 3.91 | 0.32 | 66 | 0.1189 | 0.28 | 0.084888889 | 0.1479 | 0 | 0 | 0.946428571 | 0.667 | 50 | NaN | NaN | Only 1 Truncal Mutation detected |
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Cancer Type | Patient | Age | Sex | No. of MRTB Samples with Abnormality of Interest | No. of MRTB Samples that CCF Metric Classified as Clonal | Targeted Abnormality | Therapeutic Intervention | PFS (Months) | PFS Ratio | Radiological RECIST (v1.1) Response | |
---|---|---|---|---|---|---|---|---|---|---|---|
Initial Therapy | Actionable Truncal Mutation-Directed Therapy | ||||||||||
NSCLC | P06 | 74 | M | 4/4 | 3/4 | EGFR T790M | T790M inhibitor | 2.5 | 25.5 | 10.2 | PR |
NSCLC | P05 | 43 | M | 3/4 | NA | EGFR T790M | T790M inhibitor | 2.1 | 3.6 | 1.71 | SD |
BC | P10 | 41 | F | 4/4 | 4/4 | PIK3CA H1047R | PI3Kα/β inhibitor | 2 | 1.9 | 0.95 | PD |
UC | P11 | 46 | F | 2/2 | 2/2 | AKT1 E17K | pan-AKT inhibitor | 4 | 6.1 | 1.53 | SD |
Panel | CCF | AF |
---|---|---|
FoundationOne | 0.92 | 0.13 |
AmpliSeq | 0.92 | 0.15 |
TruSight | 0.96 | 0.13 |
WES | 1 | 0.16 |
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Share and Cite
Heong, V.; Tay, D.; Goh, S.E.; Wee, B.; Tan, T.Z.; Soo, R.; Pang, B.; Lim, D.; Gopinathan, A.; Ow, S.; et al. Whole Exome Sequencing of Multi-Regional Biopsies from Metastatic Lesions to Evaluate Actionable Truncal Mutations Using a Single-Pass Percutaneous Technique. Cancers 2020, 12, 1599. https://doi.org/10.3390/cancers12061599
Heong V, Tay D, Goh SE, Wee B, Tan TZ, Soo R, Pang B, Lim D, Gopinathan A, Ow S, et al. Whole Exome Sequencing of Multi-Regional Biopsies from Metastatic Lesions to Evaluate Actionable Truncal Mutations Using a Single-Pass Percutaneous Technique. Cancers. 2020; 12(6):1599. https://doi.org/10.3390/cancers12061599
Chicago/Turabian StyleHeong, Valerie, Darwin Tay, Shane Ee Goh, Bernard Wee, Tuan Zea Tan, Ross Soo, Brendan Pang, Diana Lim, Anil Gopinathan, Samuel Ow, and et al. 2020. "Whole Exome Sequencing of Multi-Regional Biopsies from Metastatic Lesions to Evaluate Actionable Truncal Mutations Using a Single-Pass Percutaneous Technique" Cancers 12, no. 6: 1599. https://doi.org/10.3390/cancers12061599