Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomassuggests different genetic mechanisms for pathogenesis of TSC lesions

Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by m utations in either TSC1 or TSC2, is characterized by the development of ham artomas in a variety of organs. Concordant with the tumor-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at loci of both TSC1 and TSC2. LOH has been documented in renal angiomyolipomas (A MLs), but loss of the wild-type allele in cortical tubers appears to be ver y uncommon. Analysis of second, somatic events in tumors for which the stat us of both TSC1 and TSC2 is known is essential for exploration of the patho genesis of TSC-lesion development. We analyzed 24 hamartomas from 10 patien ts for second-hit mutations, by several methods, including LOH, scanning of all exons of both TSC1 and TSC2, promoter methylation of TSC2, and clonali ty analysis. Our results document loss of the wild-type allele in six of se ven AMLs, without evidence of the inactivation of the second allele in many of the other lesions, including tumors that appear to be clonally derived. Laser-capture microdissection further demonstrated loss of the second alle le in all three cellular components of an AML. This study thus provides evi dence that, in both TSC1 and TSC2, somatic mutations resulting in the loss of wild-type alleles may not be necessary in some tumor types-and that othe r mechanisms may contribute to tumorigenesis in this setting.