Defining the DNA damage repair (DDR) genomic landscape of urothelial carcinoma of the bladder (UCB).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 502-502 ◽  
Author(s):  
Shawn Dason ◽  
Victor McPherson ◽  
Min Yuen Teo ◽  
Sumit Isharwal ◽  
François Audenet ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Low Grade ◽  
High Grade ◽  
Missense Mutations ◽  
Sequencing Data ◽  
Disease Spectrum ◽  
Exon Capture ◽  
Platinum Based Chemotherapy ◽  
Unknown Significance ◽  
Carcinoma Of The Bladder

502 Background: Impaired DDR is associated with response to platinum-based chemotherapy. Several genomically directed trials have been proposed using DDR alteration status for enrolment. In this study, we characterized the deleterious DDR alteration (DDRa) landscape of UCB across various clinical states. Methods: Targeted exon capture and sequencing of at least 341 cancer-associated genes was performed prospectively on 451 UCB specimens (MSK-IMPACT assay). We assessed sequencing data for deleterious alterations in 34 genes representing canonical DDR pathways. Deleterious alterations included truncating mutations, homozygous deletions, and functionally validated missense mutations. Results: Table 1. In NMIBC, deleterious DDRa were enriched in high-grade disease ([39/136, 28.7%] high grade vs. low-grade [2/28, 7.1%]; p=0.02). The frequency of deleterious DDRa in chemo-naïve MIBC was enriched relative to unmatched post-neoadjuvant chemotherapy (NAC) residual MIBC ([33/112, 29.5%] vs. [8/55, 14.5%]; p=0.01). Patients with metastatic disease had similar rates of deleterious DDRa to MIBC ([31/116, 26.7%] vs. [33/112, 29.5%]). The percentage of patients having any type of DDR alteration was similar across states. The proportion of patients with a deleterious DDRa relative to any DDRa was 41/77 (53.2%) in NMIBC, 33/65 (50.8%) in chemo-naïve MIBC, 8/27(29.6%) in post-NAC residual MIBC, and 31/68 (45.6%) in metastatic disease. Conclusions: DDRa are found across the UCB disease spectrum. ERCC2 and ATM are the most common DDRa although alterations were seen in most other DDR genes. Many alterations are of unknown significance and further characterization is needed to develop genomically directed treatment. [Table: see text]

Uterine Sarcomas: Histology and Its Implications on Therapy

2012 ◽  
pp. 356-361 ◽  
Author(s):  
Martee L. Hensley
Keyword(s):  
High Risk ◽  
Metastatic Disease ◽  
Objective Response ◽  
The United States ◽  
Good Prognosis ◽  
Uterine Sarcoma ◽  
Low Grade ◽  
High Grade ◽  
Limited Disease ◽  
Uterine Sarcomas

Overview: Uterine sarcomas are rare cancers, they comprise only 5% of all uterine malignancies. There are about 2,000 cases of uterine sarcoma diagnosed annually in the United States. Uterine sarcomas may be categorized as either favorable-risk, low-grade malignancies with a relatively good prognosis or as poor-risk, high-grade cancers that carry a high risk for tumor recurrence and disease progression. Expert histologic review is critical for appropriate diagnosis and management. Uterine sarcoma histologies considered to carry a more favorable prognosis include low-grade endometrial stromal sarcomas and adenosarcomas. The high-grade sarcomas include high-grade leiomyosarcomas, high-grade undifferentiated endometrial sarcomas, and adenosarcomas with sarcomatous overgrowth. The favorable histology, low-grade uterine sarcomas may be cured with surgical resection of uterus-limited disease. These tumors are often hormone-sensitive, and treatment with hormonal therapies may be efficacious for patients with advanced, unresectable disease. High-grade uterine leiomyosarcomas and undifferentiated endometrial sarcomas carry a high risk for recurrence, even after complete resection of uterus-limited disease. No adjuvant intervention has been shown to improve survival outcomes. Advanced, metastatic disease is generally treated with systemic cytotoxic therapies, which may result in objective response but is not curative. Selected patients with isolated metastatic disease and a long disease-free interval may benefit from metastatectomy.

Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score to differentiate between high-grade and low-grade transitional cell carcinoma of the bladder.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 572-572
Author(s):  
Shaheen Riadh Alanee ◽  
Zade Roumayah ◽  
Musatafa Deebajah ◽  
James O. Peabody ◽  
Rodrigo Mora ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Bladder Cancer ◽  
Single Cell ◽  
Transitional Cell ◽  
Low Grade ◽  
High Grade ◽  
Median Score ◽  
Adaptive Genetic Algorithms ◽  
Cell Flow Cytometry ◽  
Carcinoma Of The Bladder

572 Background: We previously showed that adaptive genetic algorithms (AGA), in combination with single-cell flow cytometry technology, can be used to develop a noninvasive urine-based score to detect bladder cancer with high accuracy. Our aim in this analysis was to investigate if that same score can differentiate between high grade (HG) and low grade (LG) transitional cell carcinoma of the bladder (BC). Methods: We collected urine samples from cystoscopy confirmed HG and LG superficial bladder cancer patients and healthy donors in an optimized urine collection media. We then examined these samples using an assay developed from AGA in combination with single-cell flow cytometry technology. Results: We examined 50 BC and 15 healthy donor urine samples. Patients were majorly White (59.2%), males (61.2%), and had HG BC (66.7%). AGA derived score of 1.1 differentiated between BCa and healthy patients with high precision (AUC 0.92). The median score was 2.8 for LG BC and 6 for LG BC. Mann-Whitney Rank Sum Test indicated that the difference between the median score of HG and LG BC was significant at P value = 0.003. The score performed well independent of patients’ sex or smoking history. Conclusions: Using single-cell technology and machine learning, we developed a new urine-based score that can potentially differentiate between HG and LG bladder cancer. Future studies are planned to validate this score.

scholarly journals TBIO-12. THE SPECTRUM OF MITOCHONDRIAl DNA (mtDNA) MUTATIONS IN PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii468-iii469
Author(s):  
Kristiyana Kaneva ◽  
Petr Triska ◽  
Daria Merkurjev ◽  
Moiz Bootwalla ◽  
Jennifer Cotter ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cns Tumors ◽  
Whole Genome Sequencing Data ◽  
Low Grade ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Mtdna Mutation ◽  
Tumor Subtypes ◽  
Mtdna Mutations

Abstract To explore the role of mitochondrial DNA mutations in pediatric CNS tumors, we analyzed 749 tumor-normal paired whole genome sequencing data sets from the Children’s Brain Tumor Tissue Consortium (CBTTC). We detected 307 somatic mtDNA mutations in 222 CNS tumors (29.6%). Most frequently observed were missense mutations (38.1%). We also detected 34 loss-of-function mutations. Different pediatric CNS tumor subtypes have distinct mtDNA mutation profiles. For categorical comparisons, we analyzed subtypes with at least 15 samples. The highest number of mtDNA mutations per tumor sample was in meningiomas (0.85), while atypical teratoid rhabdoid tumors (ATRTs) had the lowest number per sample (0.18). High-grade gliomas had a higher number of mtDNA mutations per sample than low-grade gliomas (0.56 vs. 0.31) (p = 0.0011), with almost twice as many missense mtDNA mutations per sample (0.22 vs. 0.13) (p < 0.001), and higher average heteroplasmy levels (11% vs. 9%). The average heteroplasmy was 10.1%, ranging from 15.6% in medulloblastoma to 6.36% in schwannoma suggesting that these are clonal alterations and not artifacts. Intriguingly, the two chordoma patients in the CBTTC database had an identical heteroplasmic m.10971G>A MT-ND4 nonsense mutation. Similarly, our patient with recurrent gliofibroma harbored the same somatic MT-ND4 synonymous variant (m.10700A>G) detected at 53% heteroplasmy in the initial tumor, 79% in the first recurrence, and 97% in the second recurrence. Although the functional consequences of these alterations are not yet understood, our findings suggest that sequencing the mtDNA genome may be used to characterize CNS tumors at diagnosis and monitor disease progression.

scholarly journals Vulvar Paget disease secondary to high-grade urothelial carcinoma with underlying massive vascular embolization and cervical involvement: case report of unusual presentation

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Walquiria Quida Salles Pereira Primo ◽  
Guttenberg Rodrigues Pereira Primo ◽  
Dunya Bachour Basilio ◽  
Karime Kalil Machado ◽  
Jesus Paula Carvalho ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Immunohistochemical Analysis ◽  
Low Grade ◽  
High Grade ◽  
Paget Disease ◽  
Careful Clinical Examination ◽  
History Of ◽  
Carcinoma Of The Bladder ◽  
Tumor Emboli ◽  
Specific Symptoms

Abstract Background Vulvar extramammary Paget disease is a rare chronic condition, that presents with non-specific symptoms such as pruritus and eczematous lesions. Because most of these lesions are noninvasive, the distinction between primary and secondary Paget disease is crucial to management. Case presentation We report an unusual case of vulvar Paget disease associated with massive dermal vascular embolization, cervicovaginal involvement and metastasis to inguinal and retroperitoneal lymph nodes. The intraepithelial vulvar lesion had a classical appearance and was accompanied by extensive component of dermal lymphovascular tumor emboli, similar to those observed in inflammatory breast carcinoma. Immunohistochemical analysis revealed that the lesion was secondary to high-grade urothelial cell carcinoma. The patient had a history of superficial low-grade papillary urothelial carcinoma of the bladder, which had appeared 2 years before the onset of vulvar symptoms. Conclusions Eczematoid vulvar lesions merit careful clinical examination and biopsy, including vulva mapping and immunohistochemistry. The information obtained may help to define and classify a particular presentation of Paget disease. Noninvasive primary lesions do not require the same aggressive approaches required for the treatment of invasive and secondary disease.

Using exon-capture, deep sequencing of high-grade bladder urothelial carcinoma to identify recurrent genetic alterations and potential therapeutic targets.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 308-308
Author(s):  
Philip H. Kim ◽  
John P. Sfakianos ◽  
Sasinya N. Scott ◽  
Gopa Iyer ◽  
Eugene K. Cha ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Deep Sequencing ◽  
Copy Number ◽  
Mapk Pathway ◽  
Genetic Alterations ◽  
Sequencing Analysis ◽  
High Grade ◽  
Missense Mutations ◽  
Exon Capture ◽  
Targeted Deep Sequencing

308 Background: Urothelial carcinoma (UC) is highly lethal malignancy with limited therapeutic options in the advanced setting. Using a targeted, deep sequencing approach, we analyzed high grade bladder tumors to determine the prevalence of known cancer genes and to identify potential targets for therapy. Methods: High-grade bladder UC frozen tumor and matched germline blood was obtained from 109 patients (pts) undergoing transurethral resection or cystectomy. Tumor and normal DNA were analyzed using IMPACT (Integrated Molecular Profiling of Actionable Cancer Targets), a next generation, exon-capture targeted deep sequencing assay designed to identify point mutations, indels, and copy number alterations in the coding regions of 300 cancer-associated genes. Results: Median age was 68 and 82 pts (75%) were male. Mean target coverage for all sequenced exons was 579X. The most commonly mutated gene was TP53 (63 pts, 58%). Alterations in genes regulating cell cycle were also prevalent, including mutations in Rb (25 pts, 23%), and copy number gains of CCND1 (19 pts, 17%) and CCNE1 (8 patients, 7%). Mutations in several chromatin remodeling genes were also highly prevalent, including KDM6A (46 pts, 42%), MLL2 (34 pts, 31%), and ARID1A (31 pts, 28%). Alterations within recognized cancer-related signaling pathways were common. PI3K pathway alterations were prevalent, with PIK3CA mutations found in 25 pts (23%), 23 of which were recurrent missense mutations. Six pts (6%) had mutations in PTEN. Mutations in TSC1 were also found in six pts (6%). Alterations in select MAPK pathway genes were common, including FGFR3 (21 pts, 19%) and ERBB2(15 pts, 14%). Conclusions: High-grade bladder UC is a genetically heterogenous disease. However, over half of the tumors analyzed in this study harbor alterations in genes that have been targeted for therapeutic benefit in other cancers. Results from our targeted exon-sequencing analysis therefore provide a compelling case for clinical trials using novel agents in UC. Moreover, this deep sequencing assay may be used clinically to prospectively identify pts for trials enriched for patients with specific alterations.

scholarly journals Low‐grade prostate cancer diverges early from high grade and metastatic disease

2014 ◽  
Vol 105 (8) ◽  
pp. 1079-1085 ◽  
Author(s):  
David J. VanderWeele ◽  
Christopher D. Brown ◽  
Jerome B. Taxy ◽  
Marc Gillard ◽  
David M. Hatcher ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Low Grade ◽  
High Grade

scholarly journals ANALYSIS OF THE EXPRESSION OF FAS/CD95 AND HSP70 IN LOW AND HIGH GRADE UROTHELIAL CELL CARCINOMA OF THE BLADDER

2017 ◽  
Vol 53 (4) ◽  
pp. 247
Author(s):  
Heryanto Heryanto ◽  
Etty Hary Kusumastuti ◽  
Anny Setijo Rahaju
Keyword(s):  
Cell Carcinoma ◽  
Transitional Cell ◽  
Urothelial Cell ◽  
Hsp70 Expression ◽  
Low Grade ◽  
High Grade ◽  
Urothelial Cell Carcinoma ◽  
Cross Sectional ◽  
Carcinoma Of The Bladder ◽  
Spearman Test

Urothelial Cell Carcinoma (UCC), also called transitional cell carcinoma of the bladder, is the most common malignancy in urinary tract. The prognosis of this disease is highly dependent on the histological grading at diagnosis. Fas/CD95 has a role in apoptotic process, whereas HSP70 has an antiapoptotic role. This study aimed to analyze the expression of Fas/CD95 and HSP70 in low grade and high grade urothelial cell carcinoma in the bladder. This was an analytic observational study with cross sectional approach. Population and sample were paraffin blocks of urothelial cell carcinoma in the Laboratory of Anatomic Pathology, Dr. Soetomo Hospital, Surabaya in the period of January 2011-December 2016. Each grading of urothelial cell carcinoma was randomly sampled. Immunohistochemystry with Fas/CD95 and HSP70 were performed. Expression of Fas/CD95 and HSP70 were assessed semiquantitatively. Expression of Fas/CD95 and HSP70  were analyzed using Mann-Whitney test and Spearman test. The results showed there was significant different in expression of Fas/CD95 and HSP70 in low and high grades in urothelial cell carcinoma. There was no significant correlation between the expression of Fas/CD95 and HSP70 in urothelial cell carcinoma.  As a conclusion, the role of CD95 and HSP70 expression can be useful as marker for the diagnosis, especially in the determination of the grade of differentiation.

BRCA1, Ki67, and β-Catenin Immunoexpression Is Not Related to Differentiation, Platinum Response, or Prognosis in Women With Low- and High-Grade Serous Ovarian Carcinoma

2018 ◽  
Vol 28 (3) ◽  
pp. 437-447 ◽  
Author(s):  
Luis Felipe Sallum ◽  
Liliana Andrade ◽  
Larissa Bastos Eloy da Costa ◽  
Susana Ramalho ◽  
Amanda Canato Ferracini ◽  
...  
Keyword(s):  
Residual Disease ◽  
International Federation ◽  
Clinicopathological Features ◽  
Low Grade ◽  
High Grade ◽  
Poor Survival ◽  
Ovarian Carcinomas ◽  
Gynecology And Obstetrics ◽  
Stage Disease ◽  
Platinum Based Chemotherapy

ObjectiveThe purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival.MethodsFor this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and β-catenin expression was assessed using tissue microarray-based immunohistochemistry.ResultsWomen with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and β-catenin did not differ between LGSOC and HGSOC (P = 0.12 and P = 1.00, respectively). The clinicopathological features and the response to platinum-based chemotherapy did not differ according to the BRCA1, Ki67, and β-catenin expression in either group. In HGSOC, only International Federation of Gynecology and Obstetrics stage was independently associated with poor survival (PFS and OS).ConclusionsKi67 expression was significantly higher in HGSOC. BRCA1 and β-catenin expression did not differ between LGSOC and HGSOC samples. BRCA1, Ki67, and β-catenin expression was neither related to clinicopathological features, response to platinum-based chemotherapy, nor survival. Only International Federation of Gynecology and Obstetrics stage remained associated with poor survival in women with HGSOC.

Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5571-5571
Author(s):  
K. M. Schmeler ◽  
C. C. Sun ◽  
D. C. Bodurka ◽  
M. T. Deavers ◽  
R. L. Coleman ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Progression Free Survival ◽  
Exploratory Laparotomy ◽  
Complete Response ◽  
Serous Carcinoma ◽  
Ca 125 ◽  
Low Grade ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Platinum Based Chemotherapy

5571 Background: Neoadjuvant chemotherapy (NACT) has been associated with significant tumor reduction prior to interval debulking surgery, enabling optimal cytoreduction in up to 50% of patients with high-grade ovarian carcinomas deemed initially unresectable. Since low-grade serous carcinoma (LGSC) appears to be relatively less chemosensitive, we sought to evaluate the outcomes of women with ovarian LGSC treated with platinum-based NACT. Methods: Using institutional databases, we identified 18 women with low-grade serous carcinomas of the ovary who were treated with neoadjuvant platinum-based chemotherapy between 1978 and 2003. Patient demographic and clinical variables were abstracted from the medical records. Progression-free survival (PFS) and overall survival (OS) were estimated using the method of Kaplan-Meier. Results: The median age at diagnosis was 44 years (range, 21 to 81 years). NACT was given for extensive or non-resectable disease in 16 patients (89%) and for unknown reasons in 2 patients (11%). Ten patients (42%) underwent exploratory laparotomy with biopsy only prior to beginning chemotherapy. A median of 6 cycles of chemotherapy was given (range, 2 to 16) and included the following regimens: platinum/taxane (n=12 patients); platinum/cyclophosphamide (n=3 patients); and platinum/leuprolide acetate (n=3 patients). Of the 13 patients who had CA-125 levels available, 8 (62%) had a ≥50% reduction between pre- and post-NACT levels. However, response, determined by radiographic survey at completion of NACT, demonstrated one patient (6%) with a complete response, no patients (0%) with a partial response, and 16 patients (89%) with stable disease. One patient (6%) was not evaluable. Fifteen patients (83%) underwent interval cytoreductive surgery, which was optimal in 8 cases (53%), suboptimal in 4 cases (27%) and unknown in 3 cases (20%). Median PFS and OS for all patients were 18.6 and 56.1 months, respectively. Conclusions: A low response rate to platinum-based NACT was observed among women with LGSC of the ovary. These findings suggest that LGSC is not as responsive to conventional chemotherapy as high-grade serous carcinoma. Prospective clinical trials, focusing specifically on LGSC, are needed to make meaningful advances for this group of patients. No significant financial relationships to disclose.

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