| Autor: |
Cheng, Zhao, Mirza, Hasan, Ennis, Darren P, Smith, Philip, Morrill Gavarró, Lena, Sokota, Chishimba, Giannone, Gaia, Goranova, Theodora, Bradley, Thomas, Piskorz, Anna, Lockley, Michelle, BriTROC-1 Investigators, Kaur, Baljeet, Singh, Naveena, Tookman, Laura A, Krell, Jonathan, McDermott, Jacqueline, Macintyre, Geoffrey, Markowetz, Florian, Brenton, James D, McNeish, Iain A |
| Přispěvatelé: |
Cheng, Zhao [0000-0002-3514-240X], Mirza, Hasan [0000-0002-6460-5290], Smith, Philip [0000-0002-9306-1747], Morrill Gavarró, Lena [0000-0002-2242-4010], Bradley, Thomas [0000-0003-0218-5021], Lockley, Michelle [0000-0002-9281-5789], Macintyre, Geoffrey [0000-0003-3906-467X], Markowetz, Florian [0000-0002-2784-5308], Brenton, James D [0000-0002-5738-6683], McNeish, Iain A [0000-0002-9387-7586], Apollo - University of Cambridge Repository |
| Rok vydání: |
2022 |
| Předmět: |
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| Popis: |
PURPOSE: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. RESULTS: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. CONCLUSIONS: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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