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Silver, Daniel P.

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Silver

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Daniel P.

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Silver, Daniel P.

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2010 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.689b8b00-9df3-40eb-ad77-21e46714255f

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    MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy
    (American Association for Cancer Research (AACR), 2015) Neupane, Manish; Clark, Allison; Landini, S.; Birkbak, N; Eklund, A. C.; Lim, E.; Culhane, Aedin; Barry, William T.; Schumacher, Sandra; Beroukhim, Rameen; Szallasi, Zoltan; Vidal, Marc; Hill, David; Silver, Daniel P.
    An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified MECP2 as a novel oncogene. MECP2 resides in a region of the Xchromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12Caddicted cell line after KRAS down-regulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.
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    Prevalence and Predictors of Loss of Wild Type BRCA1 in Estrogen Receptor Positive and Negative BRCA1-Associated Breast Cancers
    (BioMed Central, 2010) Fetten, Katharina; Yassin, Yosuf; Buraimoh, Ayodele; Kim, Ji-Young; Legare, Robert D; Tung, Nadine; Miron, A; Schnitt, Stuart; Gautam, Shiva; Kaplan, Jennifer; Szasz, Attila M.; Tian, R; Wang, Zhigang C.; Collins, Laura; Brock, Jane; Krag, Karen; Sgroi, Dennis; Ryan, Paula D.; Silver, Daniel P.; Garber, Judy; Richardson, Andrea
    Introduction: The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers. Methods: Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers. Results: Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞). Conclusions: We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.