Reannotation and Analysis of Clinical and Chemotherapy Outcomes in the Ovarian Data Set From The Cancer Genome Atlas

2018 ◽  
pp. 1-16 ◽  
Author(s):  
Victor M. Villalobos ◽  
Yan C. Wang ◽  
Branimir I. Sikic

Purpose The ovarian cancer data set from The Cancer Genome Atlas integrates genomic and proteomic data with clinical annotations based on chart abstractions. We aimed to develop an algorithm to create a matching, more accessible clinical data set cataloging time to treatment failure (TTF) of sequential lines of treatment in patients with serous ovarian cancers. Materials and Methods The master data set of 587 patients with serous ovarian cancer was condensed into a more homogeneous and clinically relevant population comprised of high-risk patients with both grade 3 cancers and stage III or IV disease, resulting in a subgroup of 450 patients. We quantified the TTF of different lines of therapy as well as different therapeutic combinations by extrapolating from the time of starting one therapy to the time of starting a subsequent therapy. Results The overall survival (OS) of patients was highly related to platinum sensitivity status, with median OS times of 56.6, 27.0, and 11.6 months in patients who had platinum-sensitive, -resistant, or -refractory disease, respectively. In high-risk patients, the median TTFs were 14.8, 10.2, 5.7, and 4.1 months with the first, second, third, and fourth lines of chemotherapy, respectively. Patients with stable disease after first-line therapy had similar OS outcomes as patients with partial remissions (34.4 v 33.7 months, respectively). Conclusion This new data set enhances the clinical annotation by providing exploitable chemotherapy benefit data that can now be paired with genomic and proteomic data within The Cancer Genome Atlas data. The major determinant of OS in this study was platinum sensitivity status. TTF decreased with each successive line of therapy. However, patients who achieved only stable disease with first-line therapy had OS similar to those with partial remission.

2018 ◽  
pp. 1-11
Author(s):  
Amin H. Nassar ◽  
Kevin Lundgren ◽  
Mark Pomerantz ◽  
Eliezer Van Allen ◽  
Lauren Harshman ◽  
...  

Purpose FGFR3-TACC3 (fibroblast growth factor receptor 3–transforming acidic coiled coil-containing protein 3) fusions have recently been identified as driver mutations that lead to the activation of FGFR3 in bladder cancer and other tumor types and are associated with sensitivity to tyrosine kinase inhibitors. We examined the clinical and molecular characteristics of patients with FGFR3-TACC3 fusions and hypothesized that they are enriched in a subset of patients with bladder cancer. Materials and Methods We correlated somatic FGFR3-TACC3 fusions with clinical and molecular features in two cohorts of patients with bladder cancer. The first cohort consisted of the muscle-invasive bladder cancer (MIBC) data set (n = 412) from The Cancer Genome Atlas. The second cohort consisted of patients with MIBC or high-grade non-MIBC at the Dana-Farber Cancer Institute that had targeted capture sequencing of a selected panel of cancer genes (n = 356). All statistical tests were two sided. The clinical response of one patient with FGFR3-TACC3 bladder cancer to an FGFR3 inhibitor was investigated. Results Overall, 751 patients with high-grade bladder cancer without FGFR3-TACC3 fusions and 17 with FGFR3-TACC3 fusions were identified in the pooled analysis of the data sets from The Cancer Genome Atlas and the Dana-Farber Cancer Institute. FGFR3-TACC3 fusions were enriched in patients age ≤ 50 years versus age 51 to 65 years versus those older than 65 years (pooled, P = .002), and were observed in four (12%) of 33 patients age ≤ 50 years in the pooled analysis. Similarly, FGFR3-TACC3 fusions were significantly more common in Asians (13%) compared with African Americans (4%) and whites (2%; pooled, P < .001), as well as in never smokers (5.6%) compared with ever smokers (1.1%; pooled, P < .001). One patient with the fusion who was treated with an FGFR3 inhibitor achieved complete remission for 10 months. Conclusion Clinical testing to identify FGFR3 fusions should be prioritized for patients with bladder cancer who are younger, never smokers, and/or Asian.


2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.


2018 ◽  
Vol Volume 11 ◽  
pp. 1-11 ◽  
Author(s):  
Chundi Gao ◽  
Huayao Li ◽  
Jing Zhuang ◽  
HongXiu Zhang ◽  
Kejia Wang ◽  
...  

2018 ◽  
Vol 17 (2) ◽  
pp. 476-487 ◽  
Author(s):  
Fengju Chen ◽  
Yiqun Zhang ◽  
Sooryanarayana Varambally ◽  
Chad J. Creighton

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