본문 바로가기
KERD
논문KCI 등재

Clinical application of whole-genome sequencing of solid tumors for precision oncology

2

조회

0

다운로드

0

인용

0

참고문헌

주제분류생화학

초록

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Abstract

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

참고문헌 (66)

  1. Malone, E. R., "Molecular profiling for precision cancer therapies", Genome Med, 12, pp.8~ (2020)
  2. Bailey, M. H., "Comprehensive characterization of cancer driver genes and mutations", Cell, 173, pp.371~385 (2018)
  3. ICGC, "TCGA Pan-Cancer Analysis of Whole Genomes Consortium", Pan-cancer analysis of whole genomes, 2020, pp.578, 82~93
  4. Garraway, L. A., "Lessons from the cancer genome", Cell, 153, pp.17~37 (2013)
  5. Slamon, D. J., "Human breast cancer : correlation of relapse and survival with amplification of the HER-2", neu oncogene, 1987, pp.235, 177~182
  6. Swain, S. M., "Targeting HER2-positive breast cancer : advances and future directions", Nat. Rev. Drug Discov, 22, pp.101~126 (2023)
  7. Wolff, A. C., "Human epidermal growth factor receptor 2 testing in breast cancer", Arch. Pathol. Lab. Med, 147, pp.993~1000 (2023)
  8. Frampton, G. M., "Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing", Nat. Biotechnol, 31, pp.1023~1031 (2013)
  9. Mosele, F., "Recommendations for the use of next-generation sequencing(NGS)for patients with metastatic cancers : a report from the ESMO Precision Medicine Working Group", Ann. Oncol, 31, pp.1491~1505 (2020)
  10. Yates, L. R., "Translational genomics: practical applications of the genomic revolution in breast cancer", Clin. Cancer Res, 23, pp.2630~2639 (2017)
  11. Abbasi, A., "Significance and limitations of the use of next generation sequencing technologies for detecting mutational signatures", DNA Repair, 107, pp.103200~ (2021)
  12. "Target-enhanced whole-genome sequencing (TE-WGS) shows clinical validity equivalent to commercially available targeted oncology panel" (2023)[URL]
  13. Nakagawa, H., "Whole genome sequencing analysis for cancer geno mics and precision medicine", Cancer Sci, 109, pp.513~522 (2018)
  14. Jung, Y., "BWA-MEME : BWA-MEM emulated with a machine learning approach", Bioinformatics, 38, pp.2404~2413 (2022)
  15. Cibulskis, K., "Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples", Nat. Biotechnol, 31, pp.213~219 (2013)
  16. Kim, S., "Strelka2 : fast and accurate calling of germline and somatic variants", Nat. Methods, 15, pp.591~594 (2018)
  17. Tate, J. G., "COSMIC : the catalogue of somatic mutations in cancer", Nucleic Acids Res, 47, pp.D941~D947 (2019)
  18. Landrum, M. J., "ClinVar : public archive of relationships among sequence variation and human phenotype", Nucleic Acids Res, 42, pp.D980~D985 (2014)
  19. Favero, F., "Sequenza : allele-specific copy number and mutation profiles from tumor sequencing data", Ann. Oncol, 26, pp.64~70 (2015)
  20. Rausch, T., "DELLY : structural variant discovery by integrated paired-end and split-read analysis", Bioinformatics, 28, pp.i333~i339 (2012)
  21. McLaren, W., "The ensembl variant effect predictor", Genome Biol, 17, pp.122~ (2016)
  22. Chakravarty, D., "OncoKB : a precision oncology knowledge base", JCO Precis. Oncol, 1, pp.1~16 (2017)
  23. Guo, Q., "The mutational signatures of formalin fixation on the human genome", Nat. Commun, 13, pp.4487~ (2022)
  24. Alexandrov, L. B., "Deciphering signatures of mutational processes operative in human cancer", Cell Rep, 3, pp.246~259 (2013)
  25. Alexandrov, L. B., "The repertoire of mutational signatures in human cancer", Nature, 578, pp.94~101 (2020)
  26. Davies, H., "HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures", Nat. Med, 23, pp.517~525 (2017)
  27. Niu, B., "MSIsensor : microsatellite instability detection using paired tumor normal sequence data", Bioinformatics, 30, pp.1015~1016 (2014)
  28. Takahashi, T., "Real-world study of next-generation sequencing diagnostic biomarker testing for patients with lung cancer in Japan", Cancer Sci, 114, pp.2524~2533 (2023)
  29. Robert, N. J., "Biomarker testing and tissue journey among patients with metastatic non-small cell lung cancer receiving first-line therapy in The US Oncology Network", Lung Cancer, 166, pp.197~204 (2022)
  30. Davoli, T., "Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy", Science, 355, pp.eaaf8399~ (2017)
  31. Cortés-Ciriano, I., "Comprehensive analysis of chromothripsis in 2, 658 human cancers using whole-genome sequencing", Nat. Genet, 52, pp.331~341 (2020)
  32. "ACMG SF Genes"[URL]
  33. Ettinger, D. S., "Non-small cell lung cancer, Version 3.2022, NCCN clinical practice guidelines in oncology", J. Natl. Compr. Canc Netw, 20, pp.497~530 (2022)
  34. Kopetz, S., "Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer", N. Engl. J. Med, 381, pp.1632~1643 (2019)
  35. André, F., "Alpelisib for PIK3CA-Mutated, hormone receptor-positive advanced breast cancer", N. Engl. J. Med, 380, pp.1929~1940 (2019)
  36. Loriot, Y., "Erdafitinib in locally advanced or metastatic urothelial carcinoma", N. Engl. J. Med, 381, pp.338~348 (2019)
  37. Shaw, A. T., "First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer", N. Engl. J. Med, 383, pp.2018~2029 (2020)
  38. Camidge, D. R., "Brigatinib versus Crizotinib in ALK-positive non-small-cell lung cancer", N. Engl. J. Med, 379, pp.2027~2039 (2018)
  39. Peters, S., "Alectinib versus Crizotinib in Untreated ALK-Positive non-small-cell lung cancer", N. Engl. J. Med, 377, pp.829~838 (2017)
  40. Lee, J. J.-K., "Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma", Cell, 177, pp.1842~1857 (2019)
  41. Xiang, Y., "Therapeutic advances of rare ALK fusions in non-small cell lung cancer", Curr. Oncol, 29, pp.7816~7831 (2022)
  42. Maio, M., "Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers : updated analysis from the phase II KEYNOTE-158 study", Ann. Oncol, 33, pp.929~938 (2022)
  43. Fizazi, K., "First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer : the phase 3 TALAPRO-2 trial", Nat. Med, 30, pp.257~264 (2024)
  44. Chi, K. N., "Niraparib and Abiraterone acetate for metastatic castration resistant prostate cancer", J. Clin. Oncol, 41, pp.3339~3351 (2023)
  45. Clarke, N. W., "Abiraterone and Olaparib for metastatic castration-resistant prostate cancer", NEJM evid, 1, pp.EVIDoa2200043~ (2022)
  46. Kim, H., "Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers", Nat. Genet, 52, pp.891~897 (2020)
  47. Subbiah, V., "FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF", FGFR alterations and advanced malignancies, 2022, pp.33, 522~533
  48. Nakamura, K., "Olaparib monotherapy for BRIP1-mutated high-grade serous endometrial cancer", JCO Precis. Oncol, 4, pp.283~290 (2020)
  49. Galland, L., "Efficacy ofplatinum-based chemotherapyin metastatic breastcancer and HRD biomarkers : utility of exome sequencing", NPJ Breast Cancer, 8, pp.28~ (2022)
  50. Huang, L., "KRAS mutation : from undruggable to druggable in cancer", Signal Transduct. Target. Ther, 6, pp.386~ (2021)
  51. Hong, D. S., "KRASG12C inhibition with sotorasib in advanced solid tumors", N. Engl. J. Med, 383, pp.1207~1217 (2020)
  52. Bekaii-Saab, T. S., "Adagrasib in advanced solid tumors harboring a KRASG12C mutation", J. Clin. Oncol, 41, pp.4097~4106 (2023)
  53. Lièvre, A., "KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer", Cancer Res, 66, pp.3992~3995 (2006)
  54. Murray, S., "Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer : an analytical database", J. Thorac. Oncol, 3, pp.832~839 (2008)
  55. Alexandrov, L. B., "Mutational signatures associated with tobacco smoking in human cancer", Science, 354, pp.618~622 (2016)
  56. Paz-Ares, L., "First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer(CheckMate 9LA) : an international, randomised, open-label, phase 3 trial", Lancet Oncol, 22, pp.198~211 (2021)
  57. Aoki, K., "Adenomatous polyposis coli(APC) : a multi-functional tumor suppressor gene", J. Cell Sci, 120, pp.3327~3335 (2007)
  58. Akhoundova, D., "The grand challenge of moving cancer whole genome sequencing into the clinic", Nat. Med, 30, pp.39~40 (2024)
  59. Druliner, B. R., "Molecular characterization of colorectal adenomas with and without malignancy reveals distinguishing genome, transcriptome and methy lome alterations", Sci. Rep, 8, pp.3161~ (2018)
  60. "Whole genome mutational analysis for tumor-informed ctDNA based MRD surveillance, treatment monitoring and biological characterization of urothelial carcinoma" (2023)[URL]
  61. Leroy, K., "Retrospective analysis of real-world data to evaluate actionability of a comprehensive molecular profiling panel in solid tumor tissue samples(REALM study)", PLoS ONE, 18, pp.e0291495~ (2023)
  62. Vogelstein, B., "Cancer genome landscapes", Science, 339, pp.1546~1558 (2013)
  63. Steuten, L., "Cost effec tiveness of multigene panel sequencing for patients with advanced non-small cell lung cancer", JCO Clin. Cancer Inf, 3, pp.1~10 (2019)
  64. Pennell, N. A., "Economic impact of next-generation sequencing versus single-gene testing to detect genomic alterations in metastatic non-small-cell lung cancer using a decision analytic model", JCO Precis. Oncol, 3, pp.1~9 (2019)
  65. Vanderpoel, J., "Total cost of testing for genomic alterations associated with next generation sequencing versus polymerase chain reaction testing strategies among patients with metastatic non-small cell lung cancer", J. Med. Econ, 25, pp.457~468 (2022)
  66. Pennisi, E., "Upstart DNA sequencers could be a"game changer"", Science, 376, pp.1257~1258 (2022)

관련 논문AI추천

Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel김렬, 노진, 구재모, 권민석, 김석휘, 김장희, 김정아, 김태환, 박성열, 박준성, 박한솔, 신종연, 안미선, 이상문, 이원철, 이정석, 이현우, 임준오, 주영석, 최용원, Brian Baek-Lok Oh, Erin Connolly-Strong, Islam Oguz Tuncay대한암학회 · Cancer Research and Treatment2025 · 제57권 제2호Utilizing Plasma Circulating Tumor DNA Sequencing for Precision Medicine in the Management of Solid Cancers김시현, 차용준, 한세원대한암학회 · Cancer Research and Treatment2023 · 제55권 제2호Landscape of Actionable Genetic Alterations Profiled from 1,071 Tumor Samples in Korean Cancer Patients강진형, 고영혜, 김상겸, 김숙영, 김열홍, 김종일, 김지훈, 김철민, 김태원, 김태유, 김형래, 노동영, 라선영, 문형곤, 박근칠, 박웅양, 심준호, 유창식, 유한석, 윤재원, 이광우, 이보람, 이세훈, 이재련, 임석아, 정경해, 정연준, 정현철, 조석기, 하상윤대한암학회 · Cancer Research and Treatment2019 · 제51권 제1호Clinical Targeted Next-Generation Sequencing Panels for Detection of Somatic Variants in Gliomas경종민, 공두식, 구하림, 김자연, 남도현, 박웅양, 배준설, 서연림, 서윤지, 설호준, 손대순, 신혜미, 이정일, 이태섭, 정제균, 정종석, 조희진, 진선휘, 최승원, 최정원, Jason K. Sa, Nayoung K.D. Kim대한암학회 · Cancer Research and Treatment2020 · 제52권 제1호Validation and Clinical Application of ONCOaccuPanel for Targeted Next-Generation Sequencing of Solid Tumors김문식, 김주희, 김지은, 박지영, 이창선, 정지윤, 홍주연대한암학회 · Cancer Research and Treatment2023 · 제55권 제2호Pan-cancer Analysis of Tumor Mutational Burden and Homologous Recombination DNA Damage Repair Using Targeted Next-Generation SequencingFang Wang, Hai-Yun Wang, Ling Deng, Tao Tang, Xiao Zhang, Xin-Hua Yang, Xu Zhang, Ya-Kang Long, Yan-Fen Feng, Ying-Qing Li, Yuan He대한암학회 · Cancer Research and Treatment2021 · 제53권 제4호

이 간행물의 다른 논문 (218건)