The STK11/LKB1 Peutz-Jegher gene is not involved in the pathogenesis of sporadic sex cord-stromal tumors, although loss of heterozygosity at 19p13.3 indicates other gene alteration in these tumors

Abstract

Germ line mutations in the STK11/LKB1 tumor-suppressor gene (chromosome 19p13.3) are responsible for the Peutz-Jeghers syndrome (PJS). PJS patients frequently develop neoplasms of various organs. Ovarian sex cord-stromal tumor (SCST) with annular tubules, which shows a characteristic morphology intermediate between granulosa cell and Sertoli cell tumors, is distinctively associated with PJS. Although somatic mutations of STK11 are reportedly rare in sporadic forms of common cancers linked to PJS, there are no available studies assessing STK11 alterations in larger series of sporadic ovarian tumors with granulosa, Sertoli or combined differentiation. We examined 29 sporadic SCSTs for loss of heterozygosity (LOH) at 19p13.3, mutation, and promoter methylation of STK11. LOH at 19p13.3 was detected in 12 of 29 (41%) SCSTs, with the highest frequency at chromosome marker D19S894, which localizes approximately 3 mb centromeric to STK11, and it was more frequent in granulosa/Sertoli-stromal cell tumors (10 of 19; 52%) than in thecoma-fibroma tumors (2 of 10; 20%). The 2 fibrothecomas harboring LOH contained sex cord elements. None of the LOH-positive SCSTs demonstrated mutations or promoter methylation of STK11. Our results indicate that LOH at 19p13.3 in sporadic SCSTs targets a gene different from STK11, and may play a role in the pathogenesis of sporadic SCSTs, especially in tumors containing sex cord derivatives.