title: Nuclear maspin expression correlates with the CpG island methylator phenotype and tumor aggressiveness in colorectal cancer.
abstract: It has been suggested that nuclear expression of maspin (mammary serine protease inhibitor; also known as SERPINB5) in colorectal cancer (CRC) is associated with proximal colonic tumor location, mucinous and poorly differentiated histology, microsatellite instability-high (MSI-H), and poor prognosis. Based on these findings, there may be a potential association between nuclear maspin expression and the CpG island methylator phenotype (CIMP) in CRC, but no study has elucidated this issue. Here, we evaluated maspin protein expression status by immunohistochemistry in 216 MSI-H CRCs. CIMP status was also determined by methylation-specific quantitative PCR method (MethyLight) using eight CIMP markers (MLH1, NEUROG1, CRABP1, CACNA1G, CDKN2A (p16), IGF2, SOCS1, and RUNX3) in 216 MSI-H CRCs. Associations between maspin expression status and various pathological, molecular, and survival data were statistically analyzed. Among the 216 MSI-H CRCs, 111 (51%) cases presented nuclear maspin-positive tumors. Nuclear maspin-positive MSI-H CRCs were significantly associated with proximal tumor location (P = 0.003), tumor budding (P < 0.001), lymphovascular invasion (P = 0.001), perineural invasion (P = 0.008), absence of peritumoral lymphoid reaction (P = 0.045), lymph node metastasis (P = 0.003), distant metastasis (P = 0.005), advanced AJCC/UICC stage (stage III/IV) (P = 0.001), and CIMP-high (CIMP-H) status (P < 0.001). Patients with nuclear maspin-positive tumors showed worse disease-free survival than patients with nuclear maspin-negative tumors (log-rank P = 0.025). In conclusion, nuclear maspin expression is molecularly associated with CIMP-H rather than MSI-H, and clinicopathologically correlates with tumor aggressiveness in CRC.
authors.affiliation: Department of Pathology, SMG-SNU Boramae Medical Center Seoul, Korea.
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine Seoul, Korea.
authors.forename: Nam-Yun
authors.initials: NY
authors.lastname: Cho
authors.affiliation: Department of Pathology, Seoul National University College of Medicine Seoul, Korea.
authors.forename: Jeong Mo
authors.initials: JM
authors.lastname: Bae
authors.affiliation: Department of Pathology, Seoul National University College of Medicine Seoul, Korea.
authors.forename: Kyung-Ju
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine Seoul, Korea.
authors.forename: Ye-Young
authors.initials: YY
authors.lastname: Rhee
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital Seongnam, Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine Seoul, Korea ; Department of Pathology, Seoul National University College of Medicine Seoul, Korea.
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D002467:Cell Nucleus / Q000737:chemistry*; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D056910:Republic of Korea; D012307:Risk Factors; D015843:Serpins / Q000032:analysis* / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C085344:SERPIN-B5; D015843:Serpins
keywords: CpG island methylator phenotype; Maspin; SERPINB5; colorectal cancer; microsatellite instability; prognosis