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STRAD in Peutz-Jeghers syndrome and sporadic cancers

¹ Department of Pathology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
² Hubrecht Laboratory, Centre for Biomedical Genetics, 3584 CT Utrecht, The Netherlands
³ Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, 3015 GE Rotterdam, The Netherlands
⁴ Department of Clinical Genetics and Human Genetics, VU University Medical Centre, 1081 BT Amsterdam, The Netherlands

Correspondence to:
Ms W W J de Leng
Academic Medical Centre, Department of Pathology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; w.w.deleng{at}amc.uva.nl Background/Aims: LKB1 is a tumour suppressor gene that is associated with Peutz-Jeghers syndrome (PJS), a rare autosomal dominant cancer predisposition syndrome. However, germline mutations in the LKB1 gene are found in only about 60% of patients with PJS, suggesting the existence of a second PJS gene. The STRAD gene, encoding an LKB1 interacting protein that activates LKB1, which subsequently leads to polarisation of cells, is an interesting candidate for a second PJS gene and a potential tumour suppressor gene in sporadic carcinomas.

Methods: The involvement of STRAD in 42 PJS associated tumours (sporadic lung, colon, gastric, and ovarian adenocarcinomas) was studied using loss of heterozygosity (LOH) analysis of eight microsatellite markers on chromosome 17, including TP53, BRCA1, and STRAD markers.

Results: Loss of the marker near the STRAD locus was seen in 13 of 29 informative cases, including all gastric adenocarcinomas. Specific LOH of the STRAD marker was found in four of 29 informative cases. For these patients all exons and exon–intron boundaries of the STRAD gene were sequenced, but no somatic mutations were identified. Furthermore, no germline STRAD mutations were found in 10 patients with PJS and family members without LKB1 germline mutation.

Conclusions: Despite the frequent occurrence of LOH in the STRAD region, these results indicate that inactivation of the STRAD gene is not essential in the sporadic adenocarcinomas studied, although it is possible that STRAD may be inactivated in different ways. In addition, no evidence was found for the hypothesis that STRAD is a second PJS susceptibility gene.

Abbreviations: IHC, immunohistochemistry; LOH, loss of heterozygosity; PJS, Peutz-Jeghers syndrome

Keywords: Peutz-Jeghers syndrome; LKB1; STRAD; loss of heterozygosity

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