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DICER1 mutations in primary central nervous system tumors: new insights into histologies, mutations, and prognosis

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Abstract

Purpose

We sought to characterize clinical outcomes for adult and pediatric patients with primary CNS tumors harboring DICER1 mutations or loss of DICER1.

Methods

We conducted a retrospective cohort study of 98 patients who were treated between 1995 and 2020 for primary CNS tumors containing DICER1 mutations or loss of DICER1 on chromosome 14q, identified by targeted next generation sequencing. Kaplan–Meier plots and log rank tests were used to analyze survival. Cox proportional-hazards model was used for univariate and multivariable analyses for all-cause mortality (ACM).

Results

Within our cohort, the most common malignancies were grade 3/4 glioma (61%), grade 1/2 glioma (17%), and CNS sarcoma (6%). Sarcoma and non-glioma histologies, and tumors with biallelic DICER1 mutations or deletions were common in the pediatric population. Mutations occurred throughout DICER1, including missense mutations in the DexD/H-box helicase, DUF283, RNaseIIIa, and RNaseIIIb domains. For patients with grade 3/4 glioma, MGMT methylation (Hazard ratio [HR] 0.35, 95% Confidence Interval [CI] 0.16–0.73, p = 0.005), IDH1 R132 mutation (HR 0.11, 95% CI 0.03–0.41, p = 0.001), and missense mutation in the DexD/H-box helicase domain (HR 0.06, 95% CI 0.01–0.38, p = 0.003) were independently associated with longer time to ACM on multivariable analyses.

Conclusion

DICER1 mutations or loss of DICER1 occur in diverse primary CNS tumors, including previously unrecognized grade 3/4 gliomas as the most common histology. While prior studies have described RNaseIIIb hotspot mutations, we document novel mutations in additional DICER1 functional domains. Within the grade 3/4 glioma cohort, missense mutation in the DexD/H-box helicase domain was associated with prolonged survival.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to privacy reasons, but are available from the corresponding author on reasonable request.

Code availability

N/A.

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Funding

KXL is funded by the NIH Loan Repayment Program L40 CA264321. DHK is supported by NIH/NINDS grant 5R01NS091620-05 and NIH/NCI grant 2P50CA165962-06A1.

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Author notes

  1. Kevin X. Liu and Helen H. Shang are co-first authors.

Authors and Affiliations

  1. Department of Radiation Oncology, Harvard Medical School, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana-Farber Cancer Institute, 450 Brookline Avenue D1622, Boston, MA, 02215-5418, USA

    Kevin X. Liu, Ayal A. Aizer, Rifaquat Rahman, Karen J. Marcus & Daphne A. Haas-Kogan

  2. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Helen H. Shang

  3. Dana Farber/Boston Children’s Cancer and Blood Disorder Center, Boston, MA, USA

    Chantel Cacciotti, Junne Kamihara, Susan N. Chi & Kee Kiat Yeo

  4. Division of Pediatric Hematology/Oncology, Western University, London, ON, Canada

    Chantel Cacciotti

  5. Albany Medical College, Albany, NY, USA

    Emily Everdell

  6. Department of Oncologic Pathology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA

    Seth Malinowski

  7. Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

    David M. Meredith & Keith L. Ligon

  8. Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA, USA

    Patrick Y. Wen

  9. Department of Pathology, Harvard Medical School Boston, Boston Children’s Hospital, 300 Longwood Ave, Bader 104, Boston, MA, 02115, USA

    Sanda Alexandrescu

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Contributions

KXL and DAH-K conceived and designed the study. KXL, HHS, CC, and EE collected the data. KXL and HHS performed the data analysis. Data interpretation was performed by KXL, HHS, SA, and DAH-K. KXL, SA, and DAH-K wrote the first version of the manuscript and prepared Fig. 1 and all tables. SM prepared Fig. 1. DMM prepared Fig. S1. All authors contributed to manuscript revision and approved the final manuscript.

Corresponding authors

Correspondence to Sanda Alexandrescu or Daphne A. Haas-Kogan.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This retrospective study was approved by the Dana-Farber Cancer Institute Institutional Review Board (Approved on 7/22/2020, Protocol #20-110).

Informed consent

For this retrospective study, a waiver of informed consent was obtained through the Dana-Farber Cancer Institute Institutional Review Board (Approved on 7/22/2020, Protocol #20-110).

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Supplementary Information

Below is the link to the electronic supplementary material.

11060_2022_3994_MOESM1_ESM.tif

Supplementary file1 (TIF 2536 kb) Fig. S1 Lollipop plot depicting all DICER1 protein variants in our cohort (n = 98) excluding deletions and splicing variants

11060_2022_3994_MOESM2_ESM.pdf

Supplementary file2 (PDF 11 kb) Fig. S2 Progression-free survival (A) and overall survival (B) stratified by WHO grade 1/2 glioma, WHO grade 3/4 glioma, and sarcoma histologies, the three most common histologies

11060_2022_3994_MOESM3_ESM.docx

Supplementary file3 (DOCX 14 kb) Table S1 Histologies of adult and pediatric patients with primary central nervous system tumors with DICER1 mutations

Supplementary file4 (DOCX 28 kb) Table S2 DICER1 mutations identified in primary central nervous system tumors

11060_2022_3994_MOESM5_ESM.docx

Supplementary file5 (DOCX 17 kb) Table S3 Univariate and multivariable analyses for progression-free survival for IDH1-wildtype glioblastoma cohort

11060_2022_3994_MOESM6_ESM.docx

Supplementary file6 (DOCX 17 kb) Table S4 Univariate and multivariable analyses for overall survival for IDH1-wildtype glioblastoma cohort

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Liu, K.X., Shang, H.H., Cacciotti, C. et al. DICER1 mutations in primary central nervous system tumors: new insights into histologies, mutations, and prognosis. J Neurooncol 157, 499–510 (2022). https://doi.org/10.1007/s11060-022-03994-w

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