Peutz-Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma.
BACKGROUND
Germline mutations of the STK11/LKB1 tumour suppressor gene (19p13.3) are responsible for Peutz-Jeghers syndrome (PJS), a rare genetic disorder, which is dominantly inherited. In addition to the typical hamartomatous gastrointestinal polyps and perioral pigmented lesions, PJS is also associated with the development of tumours in various sites. No specific follow up has yet been evaluated for gene carriers. Furthermore, genetic heterogeneity has been reported, which makes genetic counselling difficult.


METHODS
We report here the analysis of the STK11/LKB1 locus in a series of 34 PJS families, combining the search for mutations and rearrangements in the coding sequence, allele specific expression tests, and linkage studies.


RESULTS
Germline deleterious mutation of the STK11/LKB1 gene were identified in 70% of cases. The hypothesis of a second PJS locus was reinforced and PJS families could be divided into two groups on the basis of the presence or absence of an identified STK11/LKB1 alteration. Analysis of clinical data indicates that the cancer associated risk is markedly different in the two groups. PJS patients with no identified STK11/LKB1 mutation are at major risk for proximal biliary adenocarcinoma, an infrequent tumour in the general population.


CONCLUSIONS
Up to 30% of PJS patients are caused by mutation in an unidentified gene that confers high susceptibility to cancer development.
Olschwang
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S
INSERM U434, 27 rue Juliette Dodu, 75010 Paris, France. olschwang@cephb.fr
Boisson
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C
Thomas
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G
D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000483:Alleles; D001661:Biliary Tract Neoplasms / Q000235:genetics*; D002648:Child; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases