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. 2021 Nov;11(11):e567.
doi: 10.1002/ctm2.567.

Integrating real-time in vivo tumour genomes for longitudinal analysis and management of glioma recurrence

Zhiyuan Sheng  1   2 , Jinliang Yu  1   2 , Kaiyuan Deng  1   2 , Yage Bu  1   2 , Shuang Wu  1   2 , Sensen Xu  1   2 , Yushuai Gao  1   2 , Qianqian Zhang  1   2 , Zhaoyue Yan  1   2 , Chaojie Bu  3   2 , Zhongcan Chen  3   2 , Jianjun Gu  3   2 , Yan Jia  4   5 , Xinya Gao  4   5 , Ajmal Zemmar  3   2 , Fitri Sumardi  3   2 , Juha Hernesniemi  3   2 , Lingfei Kong  6 , Gang Liu  7 , Ming Li  1   2 , Meiyun Wang  8 , Tianxiao Li  3   2 , Xingyao Bu  1   2
Affiliations

Integrating real-time in vivo tumour genomes for longitudinal analysis and management of glioma recurrence

Zhiyuan Sheng et al. Clin Transl Med. 2021 Nov.
No abstract available

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Conflict of interest statement

The authors have no conflict of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Circulating tumour DNA and malignant cells in tumour in situ fluid (TISF) and cerebrospinal fluid (CSF). (A) Variant allele fractions (VAFs) of mutations in the TISF. Thirty‐six patients were divided into three groups: 'Naive' included six patients who had not received radiation and chemotherapy after surgery, 'stable' contained 14 patients who were at the progression‐free stage on MRI, and 'relapse' referred to 16 patients who suffered tumour progression or relapse on MRI. p values using the Mann–Whitney test were significant (all p < 0.0001) for the comparison between any two of the groups. (B) We further analyzed genetic alterations in the 'naive' group. Matched tissue‐TISF (n = 6) shared 12 mutations, and the remaining 108 were private to the TISF. VAFs of shared mutations were statistically higher than that of TISF private alternations (p < 0.0001, Mann–Whitney test). The shared mutations probably represented the residue of the resected tumour, and the TISF private ones could contribute to the spatial genomic architecture of primary gliomas. (C and D) In our cohort, detectable CSF ctDNA was associated with radiographic features including tumour touching the CSF space (p = 0.0048) and tumour progression (p < 0.005, Mann–Whitney test). (E) TISF and CSF ctDNA displayed similar genomic profiles of glioma in four patients. The MRIs were taken at the CSF collection. The heat maps showed the similarity of mutations in matched TISF and CSF. For the patient 10, 189 and 264 mutations were detected in the TISF and the CSF, respectively. The overall VAFs in both samples were statistically comparable (p = 0.6821, Mann–Whitney test). The seeming divergences in the two samples might be caused by the time lapse and mismatch repair (MMR) function deficiency (also see Figure 3). “X” in the boxes means 'not detected'. (F) Malignant cells in the TISF and CSF of representative cases. MRIs were taken at the cytologic analysis. Abbreviations: Astro, astrocytoma; GBM, glioblastoma; Oligo, oligodendroglioma
FIGURE 2
FIGURE 2
Comparisons of tumour DNA between tumour in situ fluid (TISF) and tumour tissue. (A) Comparison of IDH status in tumour and TISF. (B) Changes in frequencies of shared mutations in the serial TISF for five patients. The second TISF sample of three patients (25, 26, 29) saw an increase in the percentage of shared mutations. For patient 29, the IDH status in the TISF dynamically changed from not‐detected to mutant and from mutant to not‐detected for patient 30. (C‐E) The numerical concordance of detected mutations between the first TISF and the tumour tissue varied considerably (0%–100%, median 10.5%) without superficial clinical relevance. (F) Alternations in TISF ctDNA harbored more multiple mutations within individual oncogenes (52.5% vs. 24.8%, p < 0.0001, chi‐square test), this might confer enhanced oncogenicity to the recurrent glioma. (G) Respective top 10 mutations in the TISF and the tumour tissue, this transformation implied the mutable genetic path to recurrence of glioma
FIGURE 3
FIGURE 3
Track the evolution patterns of glioma with combined samples. (A) The glioma progressed following a linear pattern, and the slight VAF increase of mutations in the cerebrospinal fluid (CSF) compared to the tumour in situ fluid (TISF) might mirror the gradual growth of the tumour. (B) The tumour hastened to relapse with known oncogenic pathways activated. As reported, the inactivation of FUBP1 can activate the oncogene MYC in oligodendroglioma, which is related to poorer progression‐free survival,, as shown in the panel of patient 29. (C‐E) TMZ‐induced hypermutation and progression of glioblastoma. (C) The clinical course of patient 10. (D) Mutational spectrum of detected 189 and 264 genetic alterations in the TISF and the CSF, respectively. (E) Hypermutation occurred in the key oncogenic pathways for glioblastoma, that is, NF1 in PI3K/AKT/mTOR pathway, CDK4 in RB pathway, and TP53 in P53 pathway, which might be related to the progression of the tumour. The mutational maps were generated using the cBioPortal website tool. Abbreviations: Astro., astrocytoma; GBM, glioblastoma; MMR, mismatch repair; N.D., not detected; Oligo., oligodendroglioma; RT: radiation therapy; TMZ, temozolomide aGermline mutation.
FIGURE 4
FIGURE 4
Cerebrospinal fluid‐tumour tissue‐tumour in situ fluid (CTT) sequencing pattern. (A) Flowchart of CTT pattern for precision management and monitoring of glioma. The pattern can put the glioma under molecular surveillance during the clinical course. (B), (C), and (D) are conceivable scenarios to explain the clinical applicability of tumour in situ fluid (TISF) and cerebrospinal fluid (CSF) for managing glioma. (B) The preoperative situation: The tumour m represents a glioma in the brain parenchyma with relatively lower burden, n and o stand for tumours abutting the CSF reservoir, while the tumour p is one located at the high‐risk region of the brainstem. The detectability of CSF ctDNA for preoperative glioma mainly depends on the tumour burden and touching CSF or not. (C) The stage of postoperatively progression‐free by imageology. Tumours q and s refer to the resected gliomas abutting or not abutting CSF, respectively. In this period, ctDNA is typically undetected in the CSF, while the routine obtaining of TISF can be utilized for the molecular monitoring of the de novo tumour recurrence. (D) means that both tumours have progressed overtly on the imaging and have certainly spread tumour DNA into the CSF. In this scenario, both samples are comparable for the real‐time in vivo genomic characterization of the glioma, while the procedure of obtaining TISF is less invasive than the lumbar puncture
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References

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