Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations.
We present three cases of genetically confirmed Gorlin syndrome with desmoplastic medulloblastoma (DMB) in whom tumor recurred despite standard therapy. One patient was found to have a novel germline missense PTCH1 mutation. Molecular analysis of recurrent tumor using fluorescent in situ hybridization (FISH) revealed PTEN and/ or PTCH1 loss in 2 patients. Whole exome sequencing (WES) of tumor in one patient revealed loss of heterozygosity of PTCH1 and a mutation of GNAS gene in its non-coding 3' -untranslated region (UTR) with corresponding decreased protein expression. While one patient died despite high-dose chemotherapy (HDC) plus stem cell rescue (ASCR) and palliative radiotherapy, two patients are currently alive for 18+ and 120+ months respectively following retrieval therapy that did not include irradiation. Infants with DMB and GS should be treated aggressively with chemotherapy at diagnosis to prevent relapse but radiotherapy should be avoided. The use of molecular prognostic markers for DMB should be routinely used to identify the subset of tumors that might have an aggressive course.
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.|Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.|Department of Surgery, Duke University Medical Center, Durham, North Carolina.
Sridharan
S
Gururangan
Department of Pediatrics, St. Jude Children's Research Hospital, Memphis, Tennessee.
Giles
G
Robinson
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
David W
DW
Ellison
Department of Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
Gang
G
Wu
Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio.
Xuelian
X
He
Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio.
Q Richard
QR
Lu
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Roger
R
McLendon
Department of Neurosurgery, Stanford University Medical Center, Stanford, California.
Gerald
G
Grant
Department of Bone Marrow Transplant, Duke University Medical Center, Durham, North Carolina.
Timothy
T
Driscoll
Department of Pediatrics, Palmetto Regional Hospital, Charleston, South Carolina.
Ronnie
R
Neuberg
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001478:Basal Cell Nevus Syndrome / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D002675:Child, Preschool; D002864:Chromogranins; D003131:Combined Modality Therapy; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs; D006801:Humans; D007167:Immunotherapy; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000628:therapy; D019635:Neurosurgical Procedures; D051059:PTEN Phosphohydrolase; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011878:Radiotherapy; D011956:Receptors, Cell Surface
D002864:Chromogranins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
Gorlin syndrome; PTCH; clinical features; medulloblastoma; mutation; whole genome sequencing