The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor ...phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.
To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 ...(KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.
BioMart Central Portal is a first of its kind, community-driven effort to provide unified access to dozens of biological databases spanning genomics, proteomics, model organisms, cancer data, ...ontology information and more. Anybody can contribute an independently maintained resource to the Central Portal, allowing it to be exposed to and shared with the research community, and linking it with the other resources in the portal. Users can take advantage of the common interface to quickly utilize different sources without learning a new system for each. The system also simplifies cross-database searches that might otherwise require several complicated steps. Several integrated tools streamline common tasks, such as converting between ID formats and retrieving sequences. The combination of a wide variety of databases, an easy-to-use interface, robust programmatic access and the array of tools make Central Portal a one-stop shop for biological data querying. Here, we describe the structure of Central Portal and show example queries to demonstrate its capabilities.
This prospective study investigated the prevalence of adenomyosis in histopathological examinations of patients who had undergone hysterectomy due to various indications in our clinic. ...Epidemiological characteristics, predisposing risk factors, symptoms and clinical findings of adenomyosis were evaluated.
A total of 298 subjects who had undergone abdominal, vaginal or laparoscopic hysterectomy with/without salpingooophorectomy between October 2003 and April 2004 in our clinic were included. Uterine specimens obtained through hysterectomy were weighed and histopathologically examined in the Pathology Department of Ege University. The study group (n = 103), cases with adenomyosis, was compared with the control group (n=195), cases without adenomyosis, with respect to the epidemiological, clinical and histopathological characteristics.
The prevalence of adenomyosis in 298 subjects was 36.2% (103). Duration of the reproductive period in patients with adenomyosis was found to be significantly longer than for those in the control group (p < 0.05). Prevalence of pelvic pain, dysmenorrhea and dyspareunia was also significantly higher in the study group (p < 0.05). Moreover, the number of cases requiring blood transfusion before the operation was significantly higher in the study group (p < 0.05) as were the rates of smoking, previous uterine surgery and nulliparity (p < 0.05). The most common gynecological condition accompanying adenomyosis was found to be uterine myoma in both groups, but the difference was not significant.
Adenomyosis is not a rare histopathological finding. Due to diagnostic and therapeutic methods which are being developed as an alternative to hysterectomy, the clinical effects of adenomyosis and its association with other gynecological conditions, adenomyosis appears to be an issue which will be more intensively investigated in the future.
Abstract
Background: We studied the associations between cancer gene alterations with clinical parameters in primary breast cancer (BC) samples of patients treated in either the FinHer or the FinXX ...adjuvant trial. These randomized trials accrued patients using similar inclusion criteria (node-positive, or node-negative with size >20 mm and PgR-) from the same centers, and had a similar control arm (3 cycles of docetaxel (T) followed by 3 cycles of CEF; T+CEF).
Methods: Mutations of 371 cancer-associated genes and copy number alterations (CNAs) of 86 genes or chromosomal regions were analyzed using next generation sequencing from the DNA extracted from formalin-fixed BCs. In FinHer, the comparator arm to T+CEF consisted of 3 cycles wkly vinorelbine (V) followed by 3 cycles of CEF (V+CEF), and in FinXX of docetaxel plus capecitabine (TX) followed by 3 cycles of cyclophosphamide, epirubicin and capecitabine (CEX; TX+CEX). Adjuvant trastuzumab was administered to patients with HER2+ BC in FinHer based on random allocation for 9 weeks with either T or V, and in FinXX to all patients after May 2005, usually for 1 yr.
Results: 1,014 BCs were analyzed for mutations and CNA alterations; 992 and 915 analyses were successful, respectively. 73.7% of the BCs were ER and/or PgR+ (cut-off 10%), 11.9% ER/PgR-/HER2+, and 14.7% triple-negative. 32 genes were mutated in ≥10 cancers, most commonly TP53 (38%), PIK3CA (33%) and GATA3 (10%); ErbB2 was mutated in 2.0% and ErbB3 in 1.3%. Mutations of genes associated with hereditary BC were frequent, CHEK2 4.8%, BRCA2 3.1%, PALB2 2.3%, BRCA1 1.7%. All 101 GATA3 mutations were found in ER/PgR+ BCs, whereas BRCA1, ErbB3, PREX2 and PIK3R1 mutations showed the strongest associations with ER/PgR- BC. TP53 and ErbB3 mutations were associated with HER2-positivity, whereas no AKT1, BRCA1 or SF3B1 mutations were detected in HER2+ BC. RB1, BRCA1, PALB2 and TP53 mutations were associated with high Ki-67%; MAP3K1, CDH1 and CBFB mutations with low Ki-67%. 70% of lobular cancers harbored mutated CDH1, whereas TP53 mutations were rare (4.5%). Presence of RAD50, PALB2, CHEK2 and TP53 were significantly associated with poor recurrence-free survival (RFS) with a hazard ratio (HR) of 4.11, 2.34, 2.22 and 1.56, respectively, whereas PIK3CA and GATA3 mutations with favorable RFS (HR 0.68 and 0.55). Lobular cancers with or without CDH1 mutation had similar RFS. The most frequently amplified genes were ErbB2 (26%), CCND1 (17%), RAD21 (14%) and c-MYC (14%). HER2+ BCs (defined by CISH or immunohistochemistry) frequently harbored amplified ErbB2 (88%), but also amplifications of ErbB3, MYB, WT1, FOXA1 and PIK3CA were associated with HER2+ BC. Amplifications of several genes significantly correlated with a negative ER/PgRstatus, the ductal histological type or high Ki-67%. In the FinXX trial subset patients with mutated TP53 had unfavorable outcome when treated with T+CEF but not when treated with TX+CEX, whereas patients with mutation in one of the 11 genes involved in DNA repair had poor outcome when treated with TX-CEX, but not when treated with T-CEF.
Conclusions: Cancer gene aberrations show varying associations with the clinical and histopathological features of BC. Such molecular variations may explain in part the variations found in the efficacy of cancer drugs between clinical trials.
Citation Format: Lauttia S, Gundem G, Huovinen R, Auvinen P, Loi S, Campbell P, Joensuu H. Genomic characterization of 992 primary breast cancers abstract. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-06.
The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within ...clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.
Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have ...identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples. Consequently, we were able to detect copy number changes, such as an interstitial deletion of BCOR, three MLL partial tandem duplications, and a novel KRAS amplification. With regards to coding mutations, we identified likely oncogenic variants in 41 of 42 samples. NPM1 mutations were the most frequent, followed by FLT3, DNMT3A and TET2. NPM1 and FLT3 indels were reported with good efficiency. We also showed that DNMT3A mutations can persist post-chemotherapy and in 2 cases studied at diagnosis and relapse, we were able to delineate the dynamics of tumor evolution and give insights into order of acquisition of variants. HaloPlex is a quick and reliable target enrichment method that can aid diagnosis and prognostic stratification of acute myeloid leukemia patients.
The purpose of this study was to compare the clinical symptoms and histopathological findings in subjects with adenomyosis uteri.
Infiltration depth and spread of adenomyotic foci together with ...clinical symptoms and findings were compared in a total of 103 subjects who had undergone hysterectomy and were diagnosed with adenomyosis uteri through histopathological examinations.
The spread of adenomyotic foci in myometrial tissues was observed to significantly increase as the depth of myometrial infiltration increased in subjects with adenomyosis (p < 0.05). It was observed that there was significantly higher myometrial infiltration depth in subjects with dysmenorrhea and severe anemia, and diffuse adenomyotic foci in subjects with menometrorrhagia (p < 0.05).
Increased infiltration depth and spread of adenomyotic foci in myometrial tissues in subjects with adenomyosis uteri were studied. When clinical symptoms and findings in subjects with adenomyosis, such as dysmenorrhea, anemia and menometrorrhagia are compared with these histopathological findings, infiltration depth and spread of adenomyotic foci appear to determine the clinical severity of adenomyosis.
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