Marina N Nikiforova

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (154)718.68 Total impact

  • Sean McDermott · Liron Pantanowitz · Marina Nikiforova · Sara Monaco ·

  • Human pathology 11/2015; DOI:10.1016/j.humpath.2015.11.004 · 2.77 Impact Factor
  • Lisa Radkay · Jenna Wolfe · Karen Schoedel · Marina Nikiforova · Yuri Nikiforov · N. Paul Ohori ·

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    ABSTRACT: Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell free DNA (cfDNA). Patients and methods: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n=43), bone (n=12) and brain metastases (n=38), and cfDNA (n=29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n=13), Y537S (n=3) and Y537C (n=1), and not for K303R, S463P or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3 to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n=5), mutations were detected in both (n=3) or in cfDNA only (n=2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases and cfDNA, suggesting that in some tumors rare ESR1 mutant clones are enriched by endocrine therapy.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-1534 · 8.72 Impact Factor
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    ABSTRACT: Conclusions: The BRAF K601E mutation is the second most common BRAF mutation after V600E found in thyroid nodules. Unlike BRAF V600E, this mutation is strongly associated with follicular-patterned cancer, particularly with the encapsulated follicular variant of PTC and may also be found in a follicular thyroid carcinoma. Overall, BRAF K601E mutant tumors show better clinical outcomes than BRAF V600E positive tumors, and preoperative BRAF K601E analysis can provide important prognostic information for use in clinical management.
    Thyroid: official journal of the American Thyroid Association 09/2015; DOI:10.1089/thy.2015.0227 · 4.49 Impact Factor
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    ABSTRACT: The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. Fifteen cases were previously tested by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not previously tested. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could only identify molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules in order to aid future classification, treatment, and clinical management recommendations.
    Pediatric and Developmental Pathology 09/2015; DOI:10.2350/15-07-1667-OA.1 · 0.87 Impact Factor
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    ABSTRACT: Background: Fine-needle aspiration (FNA) cytology is a common approach to evaluate thyroid nodules. It offers definitive diagnosis of a benign or malignant nodule in the majority of cases. However, 10-25% of nodules yield one of three indeterminate cytologic diagnoses, leading to suboptimal management of these patients. Atypia of undetermined significance/follicular lesion of undermined significance (AUS/FLUS) is a common indeterminate diagnosis, with the cancer risk ranging from 6% to 48%. This study assessed whether a multi-gene next-generation sequencing (NGS) assay can offer significant improvement in diagnosis in AUS/FLUS nodules. Methods: From May 2014 to March 2015, 465 consecutive FNA samples with the cytologic diagnosis of AUS/FLUS underwent prospective molecular testing using the ThyroSeq v2.1 panel. The panel included 14 genes analyzed for point mutations and 42 types of gene fusions occurring in thyroid cancer. In addition, eight genes were assessed for expression in order to evaluate the cell composition of FNA samples. Ninety-eight (21%) of these nodules had definitive surgical (n = 96) or nonsurgical (n = 2) follow-up and were used to determine the assay performance. Results: Among 465 AUS/FLUS nodules, three were found to be composed of parathyroid cells and 462 of thyroid follicular cells. Of the latter, 31 (6.7%) were positive for mutations. The most frequently mutated genes were NRAS and HRAS, and overall point mutations in seven different genes and five types of gene fusions were identified in these nodules. Among 98 nodules with known outcome, histologic analysis revealed 22 (22.5%) cancers. ThyroSeq v2.1 was able to classify 20/22 cancers correctly, showing a sensitivity of 90.9% [confidence interval (CI) 78.8-100], specificity of 92.1% [CI 86.0-98.2], positive predictive value of 76.9% [CI 60.7-93.1], and negative predictive value of 97.2% [CI 78.8-100], with an overall accuracy of 91.8% [CI 86.4-97.3]. Conclusions: The results of the study demonstrate that the ThyroSeq v2.1 multi-gene NGS panel of molecular markers provides both high sensitivity and high specificity for cancer detection in thyroid nodules with AUS/FLUS cytology, which should allow improved management for these patients.
    Thyroid: official journal of the American Thyroid Association 09/2015; DOI:10.1089/thy.2015.0305 · 4.49 Impact Factor
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    ABSTRACT: To correlate thyroid cancer genotype with histology and outcomes. The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.
    Annals of surgery 09/2015; 262(3):519-525. DOI:10.1097/SLA.0000000000001420 · 8.33 Impact Factor
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    ABSTRACT: Background: Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease. Methods: We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated. Cultured cell identity was confirmed by demonstration of the same NRAS mutation found in the original lesions and by immunophenotyping. Nevomelanocytic spheroids were treated with inhibitors of specific mediators of the NRAS signaling pathway (vemurafenib, MEK162, GDC0941, and GSK2126458). Drug sensitivity and cell viability were assessed. Results: Cultured cells were growth-factor dependent, grew as spheroids on Geltrex matrix, and maintained their clonogenicity in vitro over passages. Skin-derived cells formed more colonies than CNS-derived cells. Inhibitors of specific mediators of the NRAS signaling pathway reduced viability of NRAS mutated cells. The highest effect was obtained with GSK2126458, showing a viability reduction below 50%. Conclusions: NRAS mutated cells derived from clinical NCM samples are capable of continuous growth as spheroid colonies in vitro and retain their genetic identity. Drugs targeting the NRAS signaling pathway reduce in vitro viability of NCM cells. NCM lesional spheroids represent a new and reliable experimental model of NCM for use in drug testing and mechanistic studies.
    Neuro-Oncology 09/2015; DOI:10.1093/neuonc/nov184 · 5.56 Impact Factor
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    ABSTRACT: Multiple endocrine neoplasias (MEN) are genetic syndromes consisting of neuroendocrine tumors in two or more organs and are further classified based upon specific genetic mutations and resulting neoplasms. MEN2 is associated with a germline mutation in the RET proto-oncogene. Though pulmonary carcinoid tumors have been described in MEN1 they have not been associated with MEN2. We report a nonsmoking male patient with known MEN2B who presented with advanced, primary pulmonary neuroendocrine carcinoma harboring only his germline RET mutation. He failed to respond to conventional chemotherapy, however responded dramatically to cabozantinib, a RET-targeted therapy approved for medullary thyroid carcinoma.
    Endocrine Related Cancer 08/2015; 22(5). DOI:10.1530/ERC-15-0307 · 4.81 Impact Factor
  • Guo-Xia Tong · Kokila Mody · Zhuo Wang · Diane Hamele-Bena · Marina N Nikiforova · Yuri E Nikiforov ·
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    ABSTRACT: Clear cell follicular carcinoma is a rare type of thyroid cancer and some with aggressive biological behavior. The cytoplasmic clearing of the neoplastic cells has been attributed to the accumulation of various substances, such as glycogen, lipid, mucin, and thyroglobulin, or distension of mitochondria or endoplasmic reticulum. However, the molecular mechanisms responsible for the characteristic appearance of the cell cytoplasm and the biological behavior remain unknown. We report here a case of aggressive clear cell follicular carcinoma of the thyroid with molecular profile using targeted next generation sequencing (NGS) that presented as a metastatic tumor in a woman with a history of breast carcinoma. The NGS data revealed the coexisting of a well-characterized loss-of-function TP53 R248Q mutation and a putative gain-of-function mutation of TSHR L272V, which was suggested by the overexpression of thyroglobulin and SLC5A5 (NIS) genes in this tumor. TP53 mutations are usually related with dedifferentiation, progression, and metastasis of thyroid carcinomas. Identification of TP53 R248Q in this tumor correlated with its aggressive clinical behavior. Gain-of-function mutation of TSHR can overstimulate the thyroid follicular cells as the elevated level of TSH does and might have contributed to the development of clear cell morphology in this tumor. This report represents the first case of clear cell follicular carcinoma of the thyroid with NGS analysis and more molecular characterization is needed to elucidate the pathogenesis and provide more prognosis-relevant information for this uncommon variant of thyroid carcinomas.
    Endocrine Pathology 08/2015; 26(4). DOI:10.1007/s12022-015-9388-1 · 1.76 Impact Factor
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    ABSTRACT: The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here, we aim to describe novel genetic findings and explain possible mechanisms resulting in the most severe form of neurocutaneous melanocytosis. Detailed histological (biopsy and post-mortem) studies, tissue culture, and high-resolution cytogenetic analysis, including chromosome and array comparative genomic hybridization, Ion AmpliSeq Cancer Panel, and Sanger sequencing, were performed on tissues from a white male who succumbed at 17 months of age to congenital melanoma associated with a bathing-trunk nevus. We also used quantitative PCR to quantitatively assess the expression of NRAS among normal cells, including fibroblast and melanocytes, as well as melanoma cells from our patient. Full autopsy documented tumors in the brain, spinal cord, lung, liver, testis, bone marrow, and, retrospectively, in the placenta. Next-generation sequencing and chromosome microarray in our patient revealed novel findings, including duplication of a mutated NRAS gene, leading to an aggressive clinical course and disseminated disease. Quantitative PCR showed a five-fold increase in NRAS expression in the melanoma cell line when compared with normal melanocytes. Finally, three amino acid-changing germline variants were detected: homozygous TP53 p.P72R, heterozygous KIT p.M541L, and homozygous KDR (VEGFR2) p.Q472H. These genes are involved in malignancy and other potentially relevant pathways, such as mast cell and melanocytic signaling, as well as angiogenesis. These findings provide novel insights into the biology of congenital melanocytic proliferations, showing that amplification of mutated NRAS seems to represent a new genetic mechanism leading to melanoma in the context of neurocutaneous melanocytosis.
    Melanoma research 08/2015; 25(5). DOI:10.1097/CMR.0000000000000188 · 2.28 Impact Factor
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    ABSTRACT: BACKGROUND Although most unsuspected thyroid carcinomas qualify as microcarcinomas (≤1 cm), larger, nontargeted carcinomas may be found also. This study evaluated the significance of these nonmicrocarcinomas (>1 cm) in the setting of a large-volume thyroid practice.METHODS Thyroid resection specimens from May 2007 to December 2012 were reviewed. For these cases, the pathologic characteristics of nontargeted carcinomas larger than 1.0 cm were evaluated. Those interpreted as intrathyroidal metastases were not included in this study. Specifically, the histologic classification, size, and molecular features were documented.RESULTSFrom a total of 4815 thyroid resections and 9279 thyroid fine-needle aspiration procedures that were performed during the study period, 27 nontargeted nonmicrocarcinomas were identified (0.6% of resection cases) in 26 patients. The histologic classifications were as follows: follicular variant of papillary carcinoma (n = 19), classic papillary carcinoma (n = 3), papillary carcinoma with oncocytic features (n = 1), tall-cell variant of papillary carcinoma (n = 2), and follicular carcinoma (n = 2). The size parameters were as follows: mean, 1.9 cm; median, 1.4 cm; and range, 1.1 to 7.0 cm. RAS and BRAF mutations were identified in 8 and 7 cases, respectively (71% of the cases tested with a 7-gene panel), whereas 6 cases showed no mutation. Molecular information was not available for 6 cases.CONCLUSIONS In the authors' experience, nontargeted thyroid nonmicrocarcinomas (>1 cm) are rare (0.6%), and the majority are low-grade carcinomas. The likelihood of finding one of the common mutations (71%) is comparable to the likelihood for thyroid carcinomas in general (∼70%). Cancer (Cancer Cytopathol) 2015. © 2015 American Cancer Society.
    Cancer Cytopathology 08/2015; DOI:10.1002/cncy.21603 · 3.35 Impact Factor
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    ABSTRACT: The uncommon diagnosis of atypical parathyroid adenoma (APA) creates a clinical conundrum for surveillance. We evaluated a large series of APA to determine long-term outcomes. Prospectively collected data were retrieved for patients with a diagnosis of histologic APA defined by presence of ≥2 criteria: clinical/intraoperative adherence, fibrotic bands, trabecular growth, or mitotic rate of >1/10 per high-power field without indisputable signs of malignancy. Follow-up was at 2 weeks, 6 months, and yearly thereafter. From 1970 to 2014, 51 patients (1.2%) with primary hyperparathyroidism had a diagnosed APA. Mean age was 56 years (range, 19-83), and 61% were women. Intraoperatively, 11 of 51 glands (22%) were adherent, requiring concurrent thyroid lobectomy. Common microscopic findings were fibrosis (78%), trabecular growth (37%), and increased mitotic count (24%); the mean APA weight was 3.14 g (range, 167 mg-38 g). Loss of heterozygosity occurred in 25 of 38 tested patients (66%) at the p21 locus in 9 cases, at CDC73 and PTEN in 6, and at RB1 in 4 cases, with mean fractional allelic loss of 24% (range, 6-79). With mean follow-up of 5 years (range, 0.5-18), no patient has developed recurrence. Over a mean follow-up of 5 years, we observed no recurrences after APA resection. Molecular features had no discernable impact, indicating that long-term follow-up may be unnecessary. Copyright © 2015 Elsevier Inc. All rights reserved.
    Surgery 07/2015; 158(4). DOI:10.1016/j.surg.2015.06.022 · 3.38 Impact Factor
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    ABSTRACT: Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P < .002). All patients with colorectal carcinomas demonstrating isolated loss of MSH6 expression had Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome-associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome-associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor. Copyright © 2015. Published by Elsevier Inc.
    Human pathology 07/2015; DOI:10.1016/j.humpath.2015.06.022 · 2.77 Impact Factor
  • Beth Dudley · Randall E Brand · Darcy Thull · Nathan Bahary · Marina N Nikiforova · Reetesh K Pai ·
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    ABSTRACT: Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression without a germline PMS2 mutation must have MLH1 mutation analysis performed.
    The American journal of surgical pathology 04/2015; Publish Ahead of Print(8). DOI:10.1097/PAS.0000000000000425 · 5.15 Impact Factor
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    ABSTRACT: Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer-related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, β-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine."
    American Journal of Surgical Pathology 02/2015; 39(6). DOI:10.1097/PAS.0000000000000410 · 5.15 Impact Factor
  • Marina N. Nikiforova · William A. LaFramboise · Yuri E. Nikiforov ·
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    ABSTRACT: Next-generation sequencing (NGS) offers simultaneous sequencing of thousands to millions of nucleic acid sequences in a massively parallel way. It provides significant advantages over the conventional sequencing technique, such as Sanger sequencing, by allowing to analyze large regions of the genome with higher sensitivity of detection of various genetic variants. Whereas large-scale genome analyses such as whole genome sequencing is essential for the discovery projects, it is more than likely that sequencing of a subset of genes or genetic regions using targeted sequencing panels will be advantageous for routine molecular diagnostics of human diseases, including cancer. Targeted amplification-based enrichment methods allow for high genome throughput at a reduced cost and offer opportunities for implementing NGS in clinical practice. This chapter discusses various approaches for targeted amplification-based NGS.
    Clinical Genomics, 01/2015: pages 57-67; , ISBN: 9780124047488
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    ABSTRACT: Abstract Abstract: NRAS and BRAF mutations occur in congenital melanocytic nevi (CMN), but results are contradictory. Sixty-six prospectively collected CMN patients were analyzed for NRAS Q61 mutations using Sanger sequencing. Negative cases were evaluated for BRAF V600E mutation. NRAS Q61 mutations affected 51 (77.3%), and BRAF V600E was found in 5 patients (7.6%). NRAS Q61 mutation affected 29/36 (80.6%) giant, 16/20 (80.0%) large, and 5/8 (62.5%) medium size CMN; BRAF mutation affected 1/20 (5%) large, and 4/36 (11.4%) giant CMN. Compared to NRAS, BRAF-mutated nevi show increased/extensive dermal and subcutaneous nodules (100% BRAF+ vs. 34.8% NRAS+) (p=0.002). NCM affected 16/66 patients (24.2%): with NRAS Q61 mutation in 12 (75.0%), and BRAF V600E in two (12.5%). Two patients were negative for both mutations (12.5%), (p=0.009). In conclusion, although NRAS Q61 mutations predominate, BRAF V600E mutation also affects patients with L/GCMN, and with NCM, a novel finding. BRAF V600E is also associated with increased extensive dermal /subcutaneous nodules. These findings open the possibility of BRAF-targeted therapy in some L/GCMN and NCM cases.
    Pediatric and Developmental Pathology 12/2014; 18(1). DOI:10.2350/14-10-1566-OA.1 · 0.87 Impact Factor
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    ABSTRACT: BACKGROUND: Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules.
    Cancer 12/2014; 120(23). DOI:10.1002/cncr.29038 · 4.89 Impact Factor

Publication Stats

7k Citations
718.68 Total Impact Points


  • 2007-2015
    • University of Pittsburgh
      • • Department of Pathology
      • • Division of Neuropathology
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Stanford University
      • Department of Radiation Oncology
      Palo Alto, California, United States
  • 2011
    • Magee-Womens Hospital
      • Department of Pathology
      Pittsburgh, Pennsylvania, United States
    • Fukushima Medical University
      Hukusima, Fukushima, Japan
  • 2009
    • Houston Methodist Hospital
      Houston, Texas, United States
  • 2005-2008
    • Cincinnati Children's Hospital Medical Center
      • Division of Pathology
      Cincinnati, Ohio, United States
  • 1998-2006
    • University of Cincinnati
      • • Department of Pathology and Laboratory Medicine
      • • Division of Endocrinology, Diabetes & Metabolism
      Cincinnati, OH, United States
  • 2003
    • Yale University
      New Haven, Connecticut, United States
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 1996
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States