PMID- 31290759
OWN - NLM
STAT- MEDLINE
DCOM- 20200409
LR  - 20200409
IS  - 1532-0979 (Electronic)
IS  - 0147-5185 (Linking)
VI  - 43
IP  - 9
DP  - 2019 Sep
TI  - Immunohistochemistry for ATRX Can Miss ATRX Mutations: Lessons From 
      Neuroblastoma.
PG  - 1203-1211
LID - 10.1097/PAS.0000000000001322 [doi]
AB  - Neuroblastoma is the most common extracranial solid tumor of childhood with a 
      median age of presentation of 17 months. A common theme in high-risk 
      neuroblastoma is maintenance of telomeres, one mechanism for which involves 
      alternate lengthening of telomeres (ALT) associated with ATRX gene mutations. 
      Mutations are believed to result in loss of ATRX protein, and therefore 
      immunohistochemistry is used to detect mutations. We screened 133 cases of 
      neuroblastoma by ATRX immunohistochemistry, and found 9 cases with partial to 
      total absence of ATRX. Sequencing for ATRX mutations detected a mutation in 1 of 
      9 cases, suggesting immunostaining was not reliable for detecting mutations. To 
      correlate immunostaining with ALT, fluorescence in situ hybridization (FISH) for 
      ALT was performed in 6 of these cases and 5 (from 4 patients) showed ALT, 
      implying impaired ATRX protein function, despite the failure to identify a 
      mutation. Two other cases with large deletions in the ATRX gene showed diffusely 
      positive staining for ATRX protein but showed ALT by FISH. Four of the 6 patients 
      with ALT-positive tumors were over 5 years old. Therefore, 29 additional patients 
      5 years old and above with ATRX-positive tumors were screened for ALT by FISH and 
      6 additional cases with ALT were detected, bringing the total to 29% (10/34) of 
      children 5 years old and above, 70% of which showed positive ATRX 
      immunohistochemistry. Patients with ATRX mutations in neuroblastoma tend to have 
      a more chronic and progressive course of disease. Screening neuroblastoma tumors 
      at diagnosis for ATRX mutations may help identify patients who might benefit from 
      personalized therapy directed against ALT. However, relaying on negative 
      immunohistochemistry for ATRX protein to identify ALT in neuroblastoma may miss a 
      significant proportion of patients. The addition of FISH for ALT as part of the 
      diagnostic workup, especially for older children (5 y old and above), would help 
      ensure that patients are correctly identified for anti-ALT therapy.
FAU - Chami, Rose
AU  - Chami R
AD  - Division of Pathology.
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, ON, Canada.
FAU - Marrano, Paula
AU  - Marrano P
AD  - Division of Pathology.
FAU - Teerapakpinyo, Chinachote
AU  - Teerapakpinyo C
AD  - Chula GenePRO Center, Research Affairs.
FAU - Arnoldo, Anthony
AU  - Arnoldo A
AD  - Division of Pathology.
FAU - Shago, Mary
AU  - Shago M
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, ON, Canada.
AD  - Division of Genome Diagnostics, The Hospital for Sick Children.
FAU - Shuangshoti, Shanop
AU  - Shuangshoti S
AD  - Chula GenePRO Center, Research Affairs.
AD  - Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, 
      Thailand.
FAU - Thorner, Paul S
AU  - Thorner PS
AD  - Division of Pathology.
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, ON, Canada.
AD  - Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, 
      Thailand.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Surg Pathol
JT  - The American journal of surgical pathology
JID - 7707904
RN  - EC 3.6.4.12 (ATRX protein, human)
RN  - EC 3.6.4.12 (X-linked Nuclear Protein)
SB  - IM
MH  - Adolescent
MH  - Child
MH  - Child, Preschool
MH  - False Negative Reactions
MH  - Female
MH  - Humans
MH  - Immunohistochemistry/*methods
MH  - Infant
MH  - Male
MH  - Mutation
MH  - Neuroblastoma/*genetics
MH  - Reproducibility of Results
MH  - X-linked Nuclear Protein/*analysis/genetics
MH  - Young Adult
EDAT- 2019/07/11 06:00
MHDA- 2020/04/10 06:00
CRDT- 2019/07/11 06:00
PHST- 2019/07/11 06:00 [pubmed]
PHST- 2020/04/10 06:00 [medline]
PHST- 2019/07/11 06:00 [entrez]
AID - 10.1097/PAS.0000000000001322 [doi]
PST - ppublish
SO  - Am J Surg Pathol. 2019 Sep;43(9):1203-1211. doi: 10.1097/PAS.0000000000001322.