7 research outputs found
INVESTIGATION OF GENETIC ALTERATIONS IN EMT SUPPRESSOR, DEAR1, THROUGH PAN-CANCER ANALYSIS AND ULTRA-DEEP TARGETED SEQUENCING IN DUCTAL CARCINOMA IN SITU
Ductal carcinoma in situ (DCIS) is thought to be one of the earliest pre-invasive form of and non-obligate precursor to invasive ductal carcinoma (IDC). There is an urgent need to identify predictive and prognostic biomarkers for breast cancers with a heightened risk of progression from DCIS to IDC. Our laboratory has previously discovered a novel TRIM family member, DEAR1 (Ductal Epithelium Associated Ring Chromosome 1, annotated as TRIM62) within chromosome 1p35.1, that is mutated and homozygously deleted in breast cancer and whose expression is downregulated/lost in DCIS. Previous work has shown that DEAR1 is a novel tumor suppressor that acts as a dominant regulator of polarity, tissue architecture, and TGFβ-driven epithelial-mesenchymal transition (EMT)1,2. Herein, I have shown by pan-cancer database analysis that chromosomal loss of DEAR1 is a moderately frequent event in multiple epithelial cancers and that targeted deletion of Dear1 in the mouse recapitulates the tumor spectrum of human tumor types undergoing DEAR1 copy number losses, including mammary tumors. Therefore, these results indicate the relevance of the Dear1 mouse model to human disease and suggest that genomic alteration of DEAR1 could play a role in the etiology of multiple cancers, including breast cancer. Because DEAR1 is downregulated in DCIS and regulates polarity and EMT, I hypothesized that DEAR1 mutations might be driver events in the progression of DCIS to IDC. Therefore, targeted ultra-deep sequencing of DEAR1 was completed in FFPE samples of 17 Pure DCIS and 17 DCIS samples associated with invasive lesions. Deep sequencing of DCIS indicate DEAR1 is mutated in 71% of DCIS. Within these samples, multiple mutations within DEAR1, including exonic variants previously discovered in IDC and novel nonsense mutations were discovered and validated. Interestingly, variants in samples of DCIS associated with an invasive component indicate few variants shared between the two components, possibly supporting an independent yet parallel evolution between DCIS and IDC. Further, functional screens were performed on a subset of mutations identified and demonstrated that mutations effect DEAR1’s regulation of tissue architecture and TGFβ signaling. Altogether, this data suggests that genomic alteration of DEAR1 is an important mechanism for its loss of function and may be of significance for future targeted therapies aimed at the pathways regulated by DEAR1
Pediatric myeloid sarcoma: a single institution clinicopathologic and molecular analysis
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Clinical and molecular features of pediatric cancer patients with Lynch syndrome
Background The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). Procedure We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. Results There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at-risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis. Conclusion Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD