Kevin X Liu1, Helen H Shang2, Chantel Cacciotti3,4, Emily Everdell5, Ayal A Aizer1, Rifaquat Rahman1, Seth Malinowski6, David M Meredith7, Junne Kamihara3, Patrick Y Wen8, Keith L Ligon7, Susan N Chi3, Karen J Marcus1, Kee Kiat Yeo3, Sanda Alexandrescu9, Daphne A Haas-Kogan10. 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. 2. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 3. Dana Farber/Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA. 4. Division of Pediatric Hematology/Oncology, Western University, London, ON, Canada. 5. Albany Medical College, Albany, NY, USA. 6. Department of Oncologic Pathology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA. 7. Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. 8. Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA. 9. Department of Pathology, Harvard Medical School Boston, Boston Children's Hospital, 300 Longwood Ave, Bader 104, Boston, MA, 02115, USA. Sanda.Alexandrescu@childrens.harvard.edu. 10. 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. dhaas-kogan@bwh.harvard.edu.
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.
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.
Authors: Jiamin Chen; Yemin Wang; Melissa K McMonechy; Michael S Anglesio; Winnie Yang; Janine Senz; Sarah Maines-Bandiera; Jamie Rosner; Genny Trigo-Gonzalez; S W Grace Cheng; Jaeyeon Kim; Martin M Matzuk; Gregg B Morin; David G Huntsman Journal: J Pathol Date: 2015-07-06 Impact factor: 7.996
Authors: M S Anglesio; Y Wang; W Yang; J Senz; A Wan; A Heravi-Moussavi; C Salamanca; S Maines-Bandiera; D G Huntsman; G B Morin Journal: J Pathol Date: 2013-02 Impact factor: 7.996
Authors: M K Wu; N Sabbaghian; B Xu; S Addidou-Kalucki; C Bernard; D Zou; A E Reeve; M R Eccles; C Cole; C S Choong; A Charles; T Y Tan; D M Iglesias; P R Goodyer; W D Foulkes Journal: J Pathol Date: 2013-06 Impact factor: 7.996
Authors: Junne Kamihara; Vera Paulson; Micheál A Breen; Theodore W Laetsch; Dinesh Rakheja; David S Shulman; Michelle L Schoettler; Catherine M Clinton; Abigail Ward; Deirdre Reidy; R Seth Pinches; Daniel A Weiser; Elizabeth A Mullen; Jaclyn Schienda; Paul A Meyers; Steven G DuBois; Jonathan A Nowak; William D Foulkes; Kris Ann P Schultz; Katherine A Janeway; Sara O Vargas; Alanna J Church Journal: Mod Pathol Date: 2020-04-14 Impact factor: 7.842
Authors: D Ashley Hill; Jennifer Ivanovich; John R Priest; Christina A Gurnett; Louis P Dehner; David Desruisseau; Jason A Jarzembowski; Kathryn A Wikenheiser-Brokamp; Brian K Suarez; Alison J Whelan; Gretchen Williams; Dawn Bracamontes; Yoav Messinger; Paul J Goodfellow Journal: Science Date: 2009-06-25 Impact factor: 47.728
Authors: L Witkowski; J Mattina; S Schönberger; M J Murray; C S Choong; D G Huntsman; J S Reis-Filho; W G McCluggage; J C Nicholson; N Coleman; G Calaminus; D T Schneider; J Arseneau; C J R Stewart; W D Foulkes Journal: Br J Cancer Date: 2013-10-17 Impact factor: 7.640