TY - JOUR
T1 - Risk Stratification of Oral Potentially Malignant Disorders in Fanconi Anemia Patients Using Autofluorescence Imaging and Cytology-On-A Chip Assay
AU - Abram, Timothy J.
AU - Pickering, Curtis R.
AU - Lang, Alexander K.
AU - Bass, Nancy E.
AU - Raja, Rameez
AU - Meena, Cynthia
AU - Alousi, Amin M.
AU - Myers, Jeffrey N.
AU - McDevitt, John T.
AU - Gillenwater, Ann M.
AU - Vigneswaran, Nadarajah
N1 - Funding Information:
Financial Support: This work was supported by the National Institutes of Health through the National Institute of Dental and Craniofacial Research (award number R01DE024392) (N.V.), The Cancer Prevention and Research Institute of Texas (award number RP101382) (J.M./N.V.), UTHealth-Center for Clinical and Translational Sciences Pilot Award (N.V./J.M./A.G.), and University of Texas M.D. Anderson Cancer Center Head and Neck SPORE Developmental Research Program Award (N.V./A.G./A.A.). The COC assay platform described in this work is currently being developed for commercial use through an SBIR Fast Track Phase I/II grant (award number R44DE025798)(J.M.). This content is solely the responsibility of the authors and does not necessarily represent or reflect the official views of the National Institutes of Health or the US government.
Publisher Copyright:
© 2018
PY - 2018/4
Y1 - 2018/4
N2 - Fanconi anemia (FA) is a hereditary genomic instability disorder with a predisposition to leukemia and oral squamous cell carcinomas (OSCCs). Hematopoietic stem cell transplantation (HSCT) facilitates cure of bone marrow failure and leukemia and thus extends life expectancy in FA patients; however, survival of hematologic malignancies increases the risk of OSCC in these patients. We developed a “cytology-on-a-chip” (COC)–based brush biopsy assay for monitoring patients with oral potentially malignant disorders (OPMDs). Using this COC assay, we measured and correlated the cellular morphometry and Minichromosome Maintenance Complex Component 2 (MCM2) expression levels in brush biopsy samples of FA patients’ OPMD with clinical risk indicators such as loss of autofluorescence (LOF), HSCT status, and mutational profiles identified by next-generation sequencing. Statistically significant differences were found in several cytology measurements based on high-risk indicators such as LOF-positive and HSCT-positive status, including greater variation in cell area and chromatin distribution, higher MCM2 expression levels, and greater numbers of white blood cells and cells with enlarged nuclei. Higher OPMD risk scores were associated with differences in the frequency of nuclear aberrations and differed based on LOF and HSCT statuses. We identified mutation of FAT1 gene in five and NOTCH-2 and TP53 genes in two cases of FA patients’ OPMD. The high-risk OPMD of a non-FA patient harbored FAT1, CASP8, and TP63 mutations. Use of COC assay in combination with visualization of LOF holds promise for the early diagnosis of high-risk OPMD. These minimally invasive diagnostic tools are valuable for long-term surveillance of OSCC in FA patients and avoidance of unwarranted scalpel biopsies.
AB - Fanconi anemia (FA) is a hereditary genomic instability disorder with a predisposition to leukemia and oral squamous cell carcinomas (OSCCs). Hematopoietic stem cell transplantation (HSCT) facilitates cure of bone marrow failure and leukemia and thus extends life expectancy in FA patients; however, survival of hematologic malignancies increases the risk of OSCC in these patients. We developed a “cytology-on-a-chip” (COC)–based brush biopsy assay for monitoring patients with oral potentially malignant disorders (OPMDs). Using this COC assay, we measured and correlated the cellular morphometry and Minichromosome Maintenance Complex Component 2 (MCM2) expression levels in brush biopsy samples of FA patients’ OPMD with clinical risk indicators such as loss of autofluorescence (LOF), HSCT status, and mutational profiles identified by next-generation sequencing. Statistically significant differences were found in several cytology measurements based on high-risk indicators such as LOF-positive and HSCT-positive status, including greater variation in cell area and chromatin distribution, higher MCM2 expression levels, and greater numbers of white blood cells and cells with enlarged nuclei. Higher OPMD risk scores were associated with differences in the frequency of nuclear aberrations and differed based on LOF and HSCT statuses. We identified mutation of FAT1 gene in five and NOTCH-2 and TP53 genes in two cases of FA patients’ OPMD. The high-risk OPMD of a non-FA patient harbored FAT1, CASP8, and TP63 mutations. Use of COC assay in combination with visualization of LOF holds promise for the early diagnosis of high-risk OPMD. These minimally invasive diagnostic tools are valuable for long-term surveillance of OSCC in FA patients and avoidance of unwarranted scalpel biopsies.
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U2 - 10.1016/j.tranon.2018.01.014
DO - 10.1016/j.tranon.2018.01.014
M3 - Article
AN - SCOPUS:85044780427
VL - 11
SP - 477
EP - 486
JO - Translational Oncology
JF - Translational Oncology
SN - 1936-5233
IS - 2
ER -