title: Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications.
abstract: Alterations in high order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer. Cohesins are a family of proteins that modulate high-order chromatin, although the role in colorectal cancer remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in colorectal cancer biology and as a biomarker focusing in particular on the increased incidence/mortality of colorectal cancer among African-Americans. Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; P = 0.001) and adenocarcinomas (75%; P = 0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n = 78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared with those who were neoplasia-free (47%; P = 0.03). From a racial perspective, colorectal cancer tissues from Caucasians had 56% higher SA1 expression than in African-Americans. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared with matched African-American subjects (73%; P = 0.003). However, as a biomarker for colorectal cancer risk, the diagnostic performance as assessed by area under ROC curve was greater in African-Americans (AUROC = 0.724) than in Caucasians (AUROC = 0.585). From a biologic perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility [micrococcal nuclease (MNase)] assays in SA1-knockdown HT29 colorectal cancer cells. The functional consequences were underscored by increased proliferation (WST-1; P = 0.0002, colony formation; P = 0.001) in the SA1-knockdown HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk stratification biomarker giving potential insights into biologic basis of racial disparities in colorectal cancer. Cancer Prev Res; 9(11); 844-54. ©2016 AACR.
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Wali
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Navneet
authors.initials: N
authors.lastname: Momi
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Mart
authors.initials: M
authors.lastname: Dela Cruz
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Audrey H
authors.initials: AH
authors.lastname: Calderwood
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Stypula-Cyrus
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Luay
authors.initials: L
authors.lastname: Almassalha
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Anuj
authors.initials: A
authors.lastname: Chhaparia
authors.affiliation: Department of Pathology, University of Chicago, Illinois.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Andrew
authors.initials: A
authors.lastname: Radosevich
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Tiwari
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Bilal
authors.initials: B
authors.lastname: Latif
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Vadim
authors.initials: V
authors.lastname: Backman
authors.affiliation: Department of Medicine, Boston University Medical Center, Boston, Massachusetts. hkroy@bu.edu.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Roy
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000208:ethnology* / Q000378:metabolism; D000236:Adenoma / Q000175:diagnosis / Q000208:ethnology* / Q000378:metabolism; D001741:Black or African American; D014408:Biomarkers, Tumor / Q000032:analysis*; D063646:Carcinogenesis; D002843:Chromatin; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000208:ethnology* / Q000378:metabolism; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D044465:White People
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; D009687:Nuclear Proteins; C486457:PDS5A protein, human