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Overexpression of CDC25B and LAMC2 mRNA and Protein in Esophageal Squamous Cell Carcinomas and Premalignant Lesions in Subjects from a High-Risk Population in China

¹ Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China; ² Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; ³ Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH; ⁴ Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; ⁵ National Center for Complementary and Alternative Medicine, NIH, Bethesda, Maryland; ⁶ Information Management Services, Inc., Silver Spring, Maryland; and ⁷ Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China

Requests for reprints: Stephen M. Hewitt, Pathology Laboratory, Advanced Technology Center, National Cancer Institute, Bethesda, MD 20892-4605. Phone: 301-496-0040; Fax: 301-402-6152. E-mail: genejock{at}helix.nih.gov or Philip R. Taylor, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 7006, MSC 7236, Bethesda, MD 20892-7236. Phone: 301-594-2930; Fax 301-402-4489. E-mail: ptaylor{at}mail.nih.gov

Molecular events associated with the initiation and progression of esophageal squamous cell carcinoma (ESCC) remain poorly understood but likely hold the key to effective early detection approaches for this almost invariably fatal cancer. CDC25B and LAMC2 are two promising early detection candidates emerging from new molecular studies of ESCC. To further elucidate the role of these two genes in esophageal carcinogenesis, we did a series of studies to (a) confirm RNA overexpression, (b) establish the prevalence of protein overexpression, (c) relate protein overexpression to survival, and (d) explore their potential as early detection biomarkers. Results of these studies indicated that CDC25B mRNA was overexpressed (2-fold overexpression in tumor compared with normal) in 64% of the 73 ESCC cases evaluated, whereas LAMC2 mRNA was overexpressed in 89% of cases. CDC25B protein expression was categorized as positive in 59% (144 of 243) of ESCC cases on a tumor tissue microarray, and nonnegative LAMC2 patterns of protein expression were observed in 82% (225 of 275) of cases. Multivariate-adjusted proportional hazard regression models showed no association between CDC25B protein expression score and risk of death [hazard ratio (HR) for each unit increase in expression score, 1.00; P = 0.90]; however, several of the LAMC2 protein expression patterns strongly predicted survival. Using the cytoplasmic pattern as the reference (the pattern with the lowest mortality), cases with a diffuse pattern had a 254% increased risk of death (HR, 3.52; P = 0.007), cases with no LAMC2 expression had a 169% increased risk of death (HR, 2.69; P = 0.009), and cases with a peripheral pattern had a 130% greater risk of death (HR, 2.30; P = 0.02). CDC25B protein expression scores in subjects with esophageal biopsies diagnosed as normal (n = 35), dysplastic (n = 23), or ESCC (n = 32) increased significantly with morphologic progression. For LAMC2, all normal and dysplastic patients had a continuous pattern of protein expression, whereas all ESCCs showed alternative, noncontinuous patterns. This series of studies showed that both CDC25B and LAMC2 overexpress RNA and protein in a significant majority of ESCC cases. The strong relation of LAMC2 pattern of protein expression to survival suggests a role in prognosis, whereas the association of CDC25B with morphologic progression indicates a potential role as an early detection marker. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1424–35)

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