Promoter hypermethylation of the potential tumor suppressor DAL‐1/4.1B gene in renal clear cell carcinoma

• Published in: International journal of cancer 2006-02, Vol.118 (4), p.916-923
• Main Authors: Yamada, Daisuke, Kikuchi, Shinji, Williams, Yuko N., Sakurai‐Yageta, Mika, Masuda, Mari, Maruyama, Tomoko, Tomita, Kyoichi, Gutmann, David H., Kakizoe, Tadao, Kitamura, Tadaichi, Kanai, Yae, Murakami, Yoshinori
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; bi‐sulfite sequencing; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - surgery; Disease-Free Survival; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Profiling; Humans; Immunohistochemistry; independent prognostic factor; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidney Neoplasms - surgery; Kidney Tubules, Proximal; Kidneys; Male; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Microfilament Proteins; Middle Aged; Neoplasm Recurrence, Local; Nephrology. Urinary tract diseases; Prognosis; Promoter Regions, Genetic; recurrence‐free survival rate; Risk Factors; Tumor Cells, Cultured; tumor suppressor gene; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Tumors; Tumors of the urinary system; two‐hit inactivation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.21450

Renal clear cell carcinoma (RCCC) is a malignant tumor with poor prognosis caused by the high incidence of metastasis to distal organs. Although metastatic RCCC cells frequently show aberrant cytoskeletal organization, the underlying mechanism has not been elucidated. DAL‐1/4.1B is an actin‐binding protein implicated in the cytoskeleton‐associated processes, while its inactivation is frequently observed in lung and breast cancers and meningiomas, suggesting that 4.1B is a potential tumor suppressor. We studied a possible involvement of 4.1B in RCCCs and evaluated it as a clinical indicator. 4.1B protein was detected in the proximal convoluted tubules of human kidney, the presumed cell of origin of RCCC. On the other hand, loss or marked reduction of its expression was observed in 10 of 19 (53%) renal cell carcinoma (RCC) cells and 12 of 19 (63%) surgically resected RCCC by reverse transcription‐PCR. Bisulfite sequencing or bisulfite SSCP analyses revealed that the 4.1B promoter was methylated in 9 of 19 (47%) RCC cells and 25 of 55 (45%) surgically resected RCCC, and inversely correlated with 4.1B expression (p < 0.0001). Aberrant methylation appeared to be a relatively early event because more than 40% of the tumors with pT1a showed hypermethylation. Furthermore, 4.1B methylation correlated with a nuclear grade (p = 0.017) and a recurrence‐free survival (p = 0.0036) and provided an independent prognostic factor (p = 0.038, relative risk 10.5). These results indicate that the promoter methylation of the 4.1B is one of the most frequent epigenetic alterations in RCCC and could predict the metastatic recurrence of the surgically resected RCCC. © 2005 Wiley‐Liss, Inc.