Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterize d by hamartomatous polyps in the gastrointestinal tract and by pigmented ma cules of the lips, buccal mucosa, and digits. Less appreciated is the fact that PJS also predisposes patients to an increased risk of gastrointestinal cancer, and pancreatic cancer has been reported in many PJS patients. it w as recently shown that germline mutations of the STK11/LKB1 gene are respon sible for PJS, We investigated the role of STK11/LKB1 in the development of pancreatic and biliary cancer in patients with and without the PJS. Ln a P JS patient having a germline splice site mutation in the STK11/KB1 gene, se quencing analysis of an intestinal polyp and pancreatic cancer from this pa tient revealed loss of the wild-type allele of the STK11/LKB1 gene in the c ancer. inactivation of STK11/KB1, by homozygous deletions or somatic sequen ce mutations coupled with loss of heterozygosity, was also demonstrated in 4-6% of 127 sporadic pancreatic and biliary adenocarcinomas. Our results de monstrate that germline and somatic genetic alterations of the STK11/LKB1 g ene may play a causal role in carcinogenesis and that the same gene contrib utes to the development of both sporadic and familial forms of cancer.