RESUMEN
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
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Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Anciano , Estudios de Cohortes , Reparación de la Incompatibilidad de ADN , Femenino , Recombinación Homóloga , Humanos , Inmunohistoquímica , Mutación , Estadificación de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Receptor ErbB-2/genética , Receptor ErbB-3/genéticaRESUMEN
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer and a frequent mammographic finding requiring treatment. Up to 25% of DCIS can recur and half of recurrences are invasive, but there are no reliable biomarkers for recurrence. We hypothesised that copy number aberrations could predict likelihood of recurrence. We analysed a cohort of pure DCIS cases treated only with wide local excision for genome-wide copy number and loss of heterozygosity using Affymetrix OncoScan MIP arrays. Cases included those without recurrence within 7 years (n = 25) and with recurrence between 1 and 5 years after diagnosis (n = 15). Pure DCIS were broadly similar in copy number changes compared with invasive breast cancer, with the consistent exception of a greater frequency of ERBB2 amplification in DCIS. There were no significant differences in age or ER status between the cases with a recurrence vs those without. Overall, the DCIS cases with recurrence had more copy number events than the DCIS without recurrence. The increased copy number appeared non-random with several genomic regions showing an increase in frequency in recurrent cases, including 20 q gain, ERBB2 amplification and 15q loss. Copy number changes may provide prognostic information for DCIS recurrence, but validation in additional cohorts is required.
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Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Recurrencia Local de Neoplasia/genética , Anciano , Femenino , Dosificación de Gen , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la PolimerasaRESUMEN
Intraepithelial carcinomas of the fallopian tube are putative precursors to high-grade serous carcinomas of the ovary and peritoneum. Molecular characterization of these early precursors is limited but could be the key to identifying tumor biomarkers for early detection. This study presents a genome-wide copy number analysis of occult fallopian tube carcinomas identified through risk-reducing prophylactic oophorectomy from three women with germline BRCA1 mutations, demonstrating that extensive genomic aberrations are already established at this early stage. We found no indication of a difference in the level of genomic aberration observed in fallopian tube carcinomas compared with high-grade serous ovarian carcinomas. These findings suggest that spread to the peritoneal cavity may require no or very little further tumor evolution, which raises the question of what is the real window of opportunity to detect high-grade serous peritoneal carcinoma arising from the fallopian tube before it spreads. Nonetheless, the similarity of the genomic aberrations to those observed in high-grade serous ovarian carcinomas suggests that genetic biomarkers identified in late-stage disease may be relevant for early detection.
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Proteína BRCA1/genética , Aberraciones Cromosómicas , Neoplasias de las Trompas Uterinas/genética , Mutación , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Using whole exome sequencing to predict aberrations in tumours is a cost effective alternative to whole genome sequencing, however is predominantly used for variant detection and infrequently utilised for detection of somatic copy number variation. RESULTS: We propose a new method to infer copy number and genotypes using whole exome data from paired tumour/normal samples. Our algorithm uses two Hidden Markov Models to predict copy number and genotypes and computationally resolves polyploidy/aneuploidy, normal cell contamination and signal baseline shift. Our method makes explicit detection on chromosome arm level events, which are commonly found in tumour samples. The methods are combined into a package named ADTEx (Aberration Detection in Tumour Exome). We applied our algorithm to a cohort of 17 in-house generated and 18 TCGA paired ovarian cancer/normal exomes and evaluated the performance by comparing against the copy number variations and genotypes predicted using Affymetrix SNP 6.0 data of the same samples. Further, we carried out a comparison study to show that ADTEx outperformed its competitors in terms of precision and F-measure. CONCLUSIONS: Our proposed method, ADTEx, uses both depth of coverage ratios and B allele frequencies calculated from whole exome sequencing data, to predict copy number variations along with their genotypes. ADTEx is implemented as a user friendly software package using Python and R statistical language. Source code and sample data are freely available under GNU license (GPLv3) at http://adtex.sourceforge.net/.
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Variaciones en el Número de Copia de ADN , Exoma , Genotipo , Neoplasias/genética , Algoritmos , Aberraciones Cromosómicas , Biología Computacional/métodos , Femenino , Genómica/métodos , Técnicas de Genotipaje , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Pérdida de Heterocigocidad , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Poliploidía , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Mucinous carcinomas represent a distinct morphological subtype which can arise from several organ sites, including the ovary, and their genetic characteristics are largely under-described. Exome sequencing of 12 primary mucinous ovarian tumours identified RNF43 as the most frequently somatically mutated novel gene, secondary to KRAS and mutated at a frequency equal to that of TP53 and BRAF. Further screening of RNF43 in a larger cohort of ovarian tumours identified additional mutations, with a total frequency of 2/22 (9%) in mucinous ovarian borderline tumours and 6/29 (21%) in mucinous ovarian carcinomas. Seven mutations were predicted to truncate the protein and one missense mutation was predicted to be deleterious by in silico analysis. Six tumours had allelic imbalance at the RNF43 locus, with loss of the wild-type allele. The mutation spectrum strongly suggests that RNF43 is an important tumour suppressor gene in mucinous ovarian tumours, similar to its reported role in mucinous pancreatic precancerous cysts.
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Adenocarcinoma Mucinoso/genética , Cistoadenoma Mucinoso/genética , Proteínas de Unión al ADN/genética , Genes Supresores de Tumor/fisiología , Mutación , Proteínas Oncogénicas/genética , Neoplasias Ováricas/genética , Adenocarcinoma Mucinoso/patología , Simulación por Computador , Cistoadenoma Mucinoso/patología , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Proteínas de Unión al ADN/metabolismo , Exoma/genética , Femenino , Humanos , Modelos Moleculares , Proteínas Oncogénicas/metabolismo , Neoplasias Ováricas/patología , Análisis de Secuencia de ADN , Ubiquitina-Proteína LigasasRESUMEN
The cohesin complex is a key player in regulating cell division. Cohesin proteins SMC1, SMC3, Rad21, and stromalin (SA), along with associated proteins Nipped-B, Pds5, and EcoI, maintain sister chromatid cohesion before segregation to daughter cells during anaphase. Recent chromatin immunoprecipitation (ChIP) data reveal extensive overlap of Nipped-B and cohesin components with RNA polymerase II binding at active genes in Drosophila. These and other data strongly suggest a role for cohesion in transcription; however, there is no clear evidence for any specific mechanisms by which cohesin and associated proteins regulate transcription. We report here a link between cohesin components and trithorax group (trxG) function, thus implicating these proteins in transcription activation and/or elongation. We show that the Drosophila Rad21 protein is encoded by verthandi (vtd), a member of the trxG gene family that is also involved in regulating the hedgehog (hh) gene. In addition, mutations in the associated protein Nipped-B show similar trxG activity i.e., like vtd, they act as dominant suppressors of Pc and hh(Mrt) without impairing cell division. Our results provide a framework to further investigate how cohesin and associated components might regulate transcription.
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Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/fisiología , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/fisiología , Proteínas de Drosophila/fisiología , Transcripción Genética , Animales , Proteínas de Ciclo Celular/clasificación , Proteínas de Unión al ADN/genética , Drosophila , Proteínas de Drosophila/clasificación , Proteínas de Drosophila/genética , Embrión no Mamífero , Regulación de la Expresión Génica , CohesinasRESUMEN
OBJECTIVE: Ovarian fibromas and adenofibromas are rare ovarian tumours. They are benign tumours composed of spindle-like stromal cells (pure fibroma) or a mixture of fibroblast and epithelial components (adenofibroma). We have previously shown that 40% of benign serous ovarian tumours are likely primary fibromas due to the neoplastic alterations being restricted to the stromal compartment of these tumours. We further explore this finding by comparing benign serous tumours to pure fibromas. RESULTS: Performing copy number aberration (CNA) analysis on the stromal component of 45 benign serous tumours and 8 pure fibromas, we have again shown that trisomy of chromosome 12 is the most common aberration in ovarian fibromas. CNAs were more frequent in the pure fibromas than the benign serous tumours (88% vs 33%), however pure fibromas more frequently harboured more than one CNA event compared with benign serous tumours. As these extra CNA events observed in the pure fibromas were unique to this subset our data indicates a unique tumour evolution. Gene expression analysis on the two cohorts was unable to show gene expression changes that differed based on tumour subtype. Exome analysis did not reveal any recurrently mutated genes.
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Fibroma , Neoplasias Ováricas , Variaciones en el Número de Copia de ADN , Exoma , Femenino , Fibroma/genética , Humanos , Neoplasias Ováricas/genética , TrisomíaRESUMEN
Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
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Adenocarcinoma Mucinoso/genética , Carcinoma Epitelial de Ovario/genética , Perfilación de la Expresión Génica/métodos , Neoplasias Ováricas/genética , Adenocarcinoma Mucinoso/clasificación , Adenocarcinoma Mucinoso/metabolismo , Carcinoma Epitelial de Ovario/clasificación , Carcinoma Epitelial de Ovario/metabolismo , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/metabolismo , Análisis de Secuencia de ADN/métodos , Análisis de SupervivenciaRESUMEN
OBJECTIVE: A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS: Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS: Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS: In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Exoma/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata/genética , Anciano , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Linaje , Pronóstico , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Low-grade fibromatosis-like spindle cell carcinomas are very rare breast carcinomas comprising <0.5% of all breast cancers. They demonstrate immunohistochemical (IHC) features of basal-like/metaplastic breast carcinomas, but the underlying molecular characteristics are unknown. We hypothesised that, as with IHC similarities, there may be common genomic alterations between spindle cell and basal-like/metaplastic carcinomas. METHODS AND RESULTS: Genomic mutational profile and genomic copy number aberration (CNA) analyses were performed on three cases of this unusual entity, and findings were compared with that reported for basal-like/metaplastic breast carcinomas. Copy number analyses by molecular inversion probe assays of the three spindle cell carcinoma samples revealed little overall genomic CNAs with only minor changes identified (fraction of the genome altered; 1.3%-6.4%), but with a common 9p21.3 loss in 2 out of 3 samples, with CDKN2A (p16) being a likely candidate. No areas of commonality were identified in an in silico analysis compared with publically available basal-like/metaplastic carcinoma copy number data. CONCLUSIONS: These tumours are characterised by low genomic instability, and share no CNAs with other metaplastic carcinomas. These findings favour this entity being a unique group genotype and belie their apparent homogeneous morphology and phenotype.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Carcinoma/genética , Fibroma/genética , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias de la Mama/química , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/patología , Carcinoma/química , Carcinoma/clasificación , Carcinoma/patología , Cromosomas Humanos Par 9 , Simulación por Computador , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Fibroma/química , Fibroma/clasificación , Fibroma/patología , Dosificación de Gen , Genes p16 , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Metaplasia , Mutación , Clasificación del Tumor , FenotipoRESUMEN
BACKGROUND: Mucinous ovarian tumors are an unusual group of rare neoplasms with an apparently clear progression from benign to borderline to carcinoma, yet with a controversial cell of origin in the ovarian surface epithelium. They are thought to be molecularly distinct from other ovarian tumors but there have been no exome-level sequencing studies performed to date. METHODS: To understand the genetic etiology of mucinous ovarian tumors and assess the presence of novel therapeutic targets or pathways, we undertook exome sequencing of 24 tumors encompassing benign (5), borderline (8) and carcinoma (11) histologies and also assessed a validation cohort of 58 tumors for specific gene regions including exons 4-9 of TP53. RESULTS: The predominant mutational signature was of C>T transitions in a NpCpG context, indicative of deamination of methyl-cytosines. As well as mutations in known drivers (KRAS, BRAF and CDKN2A), we identified a high percentage of carcinomas with TP53 mutations (52 %), and recurrent mutations in RNF43, ELF3, GNAS, ERBB3 and KLF5. CONCLUSIONS: The diversity of mutational targets suggests multiple routes to tumorigenesis in this heterogeneous group of tumors that is generally distinct from other ovarian subtypes.
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Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors.
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Biomarcadores de Tumor/genética , Cistadenocarcinoma Seroso/genética , Exoma/genética , Perfilación de la Expresión Génica , Variación Genética/genética , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/patología , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Targeted resequencing by massively parallel sequencing has become an effective and affordable way to survey small to large portions of the genome for genetic variation. Despite the rapid development in open source software for analysis of such data, the practical implementation of these tools through construction of sequencing analysis pipelines still remains a challenging and laborious activity, and a major hurdle for many small research and clinical laboratories. We developed TREVA (Targeted REsequencing Virtual Appliance), making pre-built pipelines immediately available as a virtual appliance. Based on virtual machine technologies, TREVA is a solution for rapid and efficient deployment of complex bioinformatics pipelines to laboratories of all sizes, enabling reproducible results. The analyses that are supported in TREVA include: somatic and germline single-nucleotide and insertion/deletion variant calling, copy number analysis, and cohort-based analyses such as pathway and significantly mutated genes analyses. TREVA is flexible and easy to use, and can be customised by Linux-based extensions if required. TREVA can also be deployed on the cloud (cloud computing), enabling instant access without investment overheads for additional hardware. TREVA is available at http://bioinformatics.petermac.org/treva/.
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Biología Computacional/métodos , Exoma/genética , Genoma Humano/genética , Análisis de Secuencia de ADN , Interfaz Usuario-Computador , Animales , Humanos , Melanoma/genética , Ratones , Mutación/genéticaRESUMEN
PURPOSE: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. EXPERIMENTAL DESIGN: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. RESULTS: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. CONCLUSION: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents.
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Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas ras/genética , Proteínas ras/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Análisis por Conglomerados , Estudios de Cohortes , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Polimorfismo de Nucleótido Simple , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
Differentiating true somatic mutations from artifacts in massively parallel sequencing data is an immense challenge. To develop methods for optimal somatic mutation detection and to identify factors influencing somatic mutation prediction accuracy, we validated predictions from three somatic mutation detection algorithms, MuTect, JointSNVMix2 and SomaticSniper, by Sanger sequencing. Full consensus predictions had a validation rate of >98%, but some partial consensus predictions validated too. In cases of partial consensus, read depth and mapping quality data, along with additional prediction methods, aided in removing inaccurate predictions. Our consensus approach is fast, flexible and provides a high-confidence list of putative somatic mutations.
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INTRODUCTION: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histologic subtype remains undetermined. Although these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. METHODS: To explore the spectrum of genomic alterations common to mucinous tumors we carried out high-resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n = 20) and borderline tumors (n = 22). RESULTS: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. CONCLUSIONS: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors carried out to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways.
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Adenocarcinoma Mucinoso , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Cistoadenoma Mucinoso , Transducción de Señal , Proteínas ras , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Cistoadenoma Mucinoso/genética , Cistoadenoma Mucinoso/patología , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Humanos , Pérdida de Heterocigocidad , Estadificación de Neoplasias , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Polimorfismo de Nucleótido Simple , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
PURPOSE: Serous ovarian carcinomas are the predominant epithelial ovarian cancer subtype and it has been widely believed that some or all of these may arise from precursors derived from the ovarian surface epithelium or fimbriae, although direct molecular evidence for this is limited. This study aimed to conduct copy number (CN) analysis using a series of benign and borderline serous ovarian tumors to identify underlying genomic changes that may be indicative of early events in tumorigenesis. EXPERIMENTAL DESIGN: High resolution CN analysis was conducted on DNA from the epithelial and fibroblast components of a cohort of benign (N = 39) and borderline (N = 24) serous tumors using the Affymetrix OncoScan assay and SNP6.0 arrays. RESULTS: CN aberrations were detected in the epithelium of only 2.9% (1 of 35) of serous cystadenomas and cystadenofibromas. In contrast, CN aberrations were detected in the epithelium of 67% (16 of 24) of the serous borderline tumors (SBT). Unexpectedly, CN aberrations were detected in the fibroblasts of 33% (13 of 39) of the benign serous tumors and in 15% (3 of 20) of the SBTs. Of the 16 cases with CN aberrations in the fibroblasts, 12 of these carried a gain of chromosome 12. CONCLUSIONS: Chromosome 12 trisomy has been previously identified in pure fibromas, supporting the concept that a significant proportion of benign serous tumors are in fact primary fibromas with an associated cystic mass. This is the first high resolution genomic analysis of benign serous ovarian tumors and has shown not only that the majority of benign serous tumors have no genetic evidence of epithelial neoplasia but that a significant proportion may be more accurately classified as primary fibromas.