Somatic mutations in the Peutz-Jegners (LKB1/STKII) gene in sporadic malignant melanomas

Germline mutations in the LKB1/STK11 gene cause characteristic hamartomas a nd freckling to develop in patients with Peutz-Jeghers syndrome (PJS), The hamartomas arise as a result of somatic "second hits" at LKB1/STK11 and the refore contain a neoplastic element, The origin of the pigmented lesions in PJS is unknown and difficult to test, as these are hardly ever biopsied, P JS patients are at increased risk of benign and malignant tumors, particula rly of the colon, breast, pancreas, testis, and ovary, although the increas ed risk for any one of these sites may be quite modest. Somatic LKB1/STK11 mutations have been found, albeit at a low frequency, in sporadic tumors of the colon, stomach, ovary, and testis, Although PJS patients are not known to have an excess of skin tumors, if the freckles of PJS patients are actu ally small, benign tumors, LKB1/STK11 mutations must provide these lesions with a selective advantage, and similar mutations might also give a selecti ve advantage to related malignant tumors, such as melanomas, We have theref ore screened 16 melanoma cell lines, 15 primary melanomas, and 19 metastase s for LKB1/STK11 mutations. Two LKB1/STK11 mutations were found: a missense change (Y49D) accompanied by allele loss in a cell line; and a missense ch ange (G135R), without a detected mutation in the other allele, in a primary tumor. Both these mutations are highly likely to be pathogenic. Novel poly morphisms, including an unusual heptanucleotide repeat, were also found in introns 2 and 3, LKB1/STK11 mutations occur in a significant minority of tu mors of several sites, including malignant melanomas.