STK11 genotyping and cancer risk in Peutz-Jeghers syndrome

eutz-Jeghers syndrome (PJS; OMIM #175200) is an autosomal dominant disorder characterised by mucocutaneous melanin pigmentation, gastrointestinal hamartomatous polyposis, and an increased risk for the development of various neoplasms.1 2 Malignancies occur both in the gastrointestinal tract and in extraintestinal sites such as the pancreas, the breast, and reproductive organs.The estimated relative cancer risk may be 15 fold higher than in the general population 1 and appears to be particularly high in women (20 fold) because of an increased risk of development of breast cancer and gynaecological malignancies.2 Germline mutations in the STK11/LKB1 gene on 19p13.3 are found in 30-70% of PJS cases, depending on the screening method, with considerable uncharacterised genetic heterogeneity remaining in this syndrome.3 4 The disease causing gene has been identified by two independent groups.5 6 Human STK11 encodes a serine/threonine protein kinase that is highly homologous to the mouse protein Lkb1 and the Xenopus kinase XEEK1, 7 8 and is expressed in all human tissues.9 The kinase domain of the human 433 amino acid protein is localised between residues 49 and 309, 7 and shows homology to the conserved catalytic core of the kinase domain common to both serine/threonine and tyrosine protein kinase family members.10 Most mutations found in PJS patients are small deletions/insertions or single base substitutions leading to an abnormal truncated/kinase inactive protein.Loss of the wild type allele in hamartomas and adenocarcinomas occurring in patients with PJS suggests that STK11 is a tumour suppressor gene.Several studies have described a role in cell cycle arrest, 11 p53 mediated apoptosis, 12 Wnt signalling, 13 14 TGF-b signalling, 15 Ras induced cell transformation, 16 and cell polarity.[17][18][19][20] Growth suppression requires phosphorylation of STK11 21 22 and was found to be caused by activation of the CDK inhibitor p21.23 Moreover, by associating with Brg1, an essential component of chromatin remodelling complexes, STK11 can induce growth arrest.24 It was found that the lack of STK11 may support tumour cell growth through the induction of vascular endothelial growth factor.25 Taken together, these data suggest that STK11 mutations may contribute to tumorigenesis through various mechanisms such as induction of angiogenesis, suppression of growth arrest, apoptosis, and loss of cell polarity.PJS is a cancer predisposing disorder; however, cancer risk may vary.Therefore, we studied whether specific STK11 mutations may confer a lower or higher cancer risk in PJS patients by examining the site and type of mutations with regard to cancer frequency and cancer type.