Spectrum of mutations in leiomyosarcomas identified by clinical targeted next-generation sequencing.

Recurrent genomic mutations in uterine and non-uterine leiomyosarcomas have not been well established. Using a next generation sequencing (NGS) panel of common cancer-associated genes, 25 leiomyosarcomas arising from multiple sites were examined to explore genetic alterations, including single nucleotide variants (SNV), small insertions/deletions (indels), and copy number alterations (CNA). Sequencing showed 86 non-synonymous, coding region somatic variants within 151 gene targets in 21 cases, with a mean of 4.1 variants per case; 4 cases had no putative mutations in the panel of genes assayed. The most frequently altered genes were TP53 (36%), ATM and ATRX (16%), and EGFR and RB1 (12%). CNA were identified in 85% of cases, with the most frequent copy number losses observed in chromosomes 10 and 13 including PTEN and RB1; the most frequent gains were seen in chromosomes 7 and 17. Our data show that deletions in canonical cancer-related genes are common in leiomyosarcomas. Further, the spectrum of gene mutations observed shows that defects in DNA repair and chromosomal maintenance are central to the biology of leiomyosarcomas, and that activating mutations observed in other common cancer types are rare in leiomyosarcomas.

Imaging of tailgut cysts.

Tailgut cysts are congenital lesions that arise from the primitive hindgut in the true embryonic tail but fail to regress during gestation. These lesions are rare and more frequently encountered later in life and more commonly in women, and are the most common primary retrorectal tumor. Tailgut cysts may be asymptomatic or cause rectal bleeding, pain, or symptoms related to mass effect on the rectum or bladder. Pathologically, tailgut cysts are typically multilocular, lined with a variety of epithelial cell types, and are most frequently benign. Imaging is the linchpin of diagnosis due risks associated with biopsy. The purpose of this pictorial review is to present the spectrum of imaging findings associated with tailgut cysts on CT and MRI with focus on the use of advanced MRI and diffusion-weighted imaging. We present case examples of tailgut cysts, their CT and MR imaging findings, and diagnostic and management considerations.

Transforming growth factor-beta can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model.

The transforming growth factor-beta (TGF-beta) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-beta is a potent inhibitor of epithelial cell proliferation, it has been widely assumed that this property underlies the tumor-suppressor effect. Here, we have used a xenograft model of breast cancer to show that endogenous TGF-beta has the potential to suppress tumorigenesis through a novel mechanism, involving effects at two distinct levels in the hierarchy of cellular progeny that make up the epithelial component of the tumor. First, TGF-beta reduces the size of the putative cancer stem or early progenitor cell population, and second it promotes differentiation of a more committed, but highly proliferative, progenitor cell population to an intrinsically less proliferative state. We further show that reduced expression of the type II TGF-beta receptor correlates with loss of luminal differentiation in a clinical breast cancer cohort, suggesting that this mechanism may be clinically relevant. At a molecular level, the induction of differentiation by TGF-beta involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-beta. These data suggest new roles for the TGF-beta pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.

Suv39h histone methyltransferases interact with Smads and cooperate in BMP-induced repression.

Smad proteins transduce signals from transforming growth factor-beta (TGF-beta) superfamily ligands to regulate the expression of target genes. In order to identify novel partners of Smad proteins in transcriptional regulation, we performed a two-hybrid screen using Smad5, a protein that is activated predominantly by bone morphogenetic protein (BMP) signaling. We identified an interaction between Smad5 and suppressor of variegation 3-9 homolog 2 (Suv39h2), a chromatin modifier enzyme. Suv39h proteins are histone methyltransferases that methylate histone H3 on lysine 9, resulting in transcriptional repression or silencing of target genes. Biochemical studies in mammalian cells demonstrated that Smad5 binds to both known mammalian isoforms of Suv39h proteins, and that Smad proteins activated by the TGF-beta signaling pathway, Smad2 and Smad3, do not bind with significant affinity. Functional studies using the muscle creatine kinase (MCK) promoter, which is suppressed by BMP signaling, demonstrate that Suv39h proteins and Smads cooperate to repress promoter activity. These data suggest a model where association of Smad proteins with Suv39h methyltransferases can repress or silence genes involved in developmental processes, and argues that inefficient gene repression may result in the alteration of the differentiated phenotype. Thus, examination of the Smad-Suv interaction may provide insight into the mechanism of phenotypic determination mediated by BMP signaling.