Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome

Germ-Line mutations of the LKB1 gene cause Peutz-Jeghers syndrome (PJS) cha racterized by mucocutaneous pigmentation, predisposition to benign hamartom as of the gastrointestinal tract and also to several types of tumors. Howev er, somatic mutations of this gene are, very rare. To examine inactivation of LKB1 by epigenetic mechanisms,,ve investigated a series of primary tumor s and canter cell lines, for hg permethylation affecting the CpG island loc ated in the 5' region of the LKB1 gene using Methylation-specific PCR (MSP) . First, we screened 51 cancer cell lines. Only three colorectal and one ce rvical carcinoma cell lines were methylated at LKB1, and loss of the LKB1 t ranscript was demonstrated. Treatment with the demethylating agent 5-aza-2' -deoxycytidine restored LKB1 expression, To address the incidence of LKB1 e pigenetic inactivation in primary tumors, we analysed colorectal, breast, g astric, pancreatic, thyroid, bladder and testicular carcinomas (n = 195), N ormal tissues from the mentioned organs were unmethylated in this region. A mong the described tumors, only one colorectal carcinoma and three testicul ar tumors displayed LKB1 promoter hypermethylation. Further study of those histological types more commonly associated with PJS, demonstrated that LKB 1 promoter hypermethylation was present in five of 11 (45%) papillary breas t carcinomas, Finally, in three patients with a strong family story suggest ive of PJS disease, abnormal LKB1 methylation was found in four of 22 (18%) hamartomatous polyps lesions. Our findings provide an alternative pathway for inactivation of the LKB1 tumor suppressor gene involving promoter hyper methylation.