scholarly journals The Genomic Landscape of Prostate Cancer Brain Metastases

2020 ◽  
Author(s):  
Antonio Rodriguez ◽  
John Gallon ◽  
Dilara Akhoundova ◽  
Sina Maletti ◽  
Alison Ferguson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Brain Metastases ◽  
Large Scale ◽  
Parp Inhibition ◽  
State Transitions ◽  
Primary Tumors ◽  
Available N ◽  
Cancer Metastases ◽  
Whole Exome ◽  
Significant Enrichment

AbstractLethal prostate cancer commonly metastasizes to bone, lymph nodes, and visceral organs but with more effective therapies, there is an increased frequency of metastases to the brain. Little is known about the genomic drivers of prostate cancer brain metastases (PCBM). To address this, we conducted a comprehensive multi-regional, genomic, and targeted transcriptomic analysis of PCBM from 28 patients. We compared whole-exome and targeted RNA sequencing with matched primary tumors when available (n = 10) and with publicly available genomic data from non-brain prostate cancer metastases (n = 416). In addition to common alterations in TP53, AR, RB1, and PTEN, we identified highly significant enrichment of mutations in NF1 (25% cases (6/28), q = 0.049, 95% CI = 2.38 – 26.52, OR = 8.37) and RICTOR (17.9% cases (5/28), q = 0.01, 95% CI = 6.74 – 480.15, OR = 43.7) in PCBM compared to non-brain prostate cancer metastases, suggesting possible activation of the druggable pathways RAS/RAF/MEK/ERK and PI3K/AKT/mTOR, respectively. Compared to non-brain prostate cancer metastases, PCBM were almost three times as likely to harbor DNA homologous repair (HR) alterations (42.9% cases (12/28), p =0.016, 95% CI = 1.17 – 6.64, OR = 2.8). When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions, 64.3% of patients (18/28) were affected. HR alterations may be critical drivers of brain metastasis that potentially provide cancer cells a survival advantage during re-establishment in a special microenvironment. We demonstrate that PCBM have genomic dependencies that may be exploitable through clinical interventions including PARP inhibition.

scholarly journals Comparative analysis of clonal evolution among patients with right-sided colon cancer, left-sided colon cancer and rectal cancer

2020 ◽  
Author(s):  
Santasree Banerjee ◽  
Xianxiang Zhang ◽  
Shan Kuang ◽  
Jigang Wang ◽  
Lei Li ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Comparative Analysis ◽  
Large Scale ◽  
Clonal Evolution ◽  
Intratumor Heterogeneity ◽  
Primary Tumors ◽  
Evolution Pattern ◽  
Whole Exome ◽  
High Depth

AbstractBackgroundTumor multi-region sequencing reveals intratumor heterogeneity (ITH) and clonal evolution which play a key role in progression and metastases of the tumor. However, large-scale high depths multiregional sequencing of colorectal cancer (CRC) has not been well studied. In addition, the comparative analysis among right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer (RC) patients as well as the study of lymph node metastasis (LN) with extranodal tumor deposits (ENTD) from evolutionary perspective remain unknown.ResultsIn this prospective study, we recruited different stages of 68 CRC patients with RCC (18), LCC (20) and RC (30). We performed high-depth whole exome sequencing (WES) of 206 tumor regions including 176 primary tumors, 19 LN and 11 ENTD samples. Our results showed ITH with a Darwinian pattern of evolution. We identified that the evolution pattern of LCC and RC was more complex and divergent than RCC, suggesting the evolutionary diversity in the initiation and progression of LCC and RC. Genetic and evolutionary evidences found that both LN and ENTD were of polyclonal in origin. Moreover, ENTD was a distinct entity from LN and evolved later.ConclusionsIn conclusion, our study showed the Darwinian pattern of evolution with differences in clonal evolution between RCC with LCC and RC.

scholarly journals Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1173 ◽  
Author(s):  
Sander Frank ◽  
Peter Nelson ◽  
Valeri Vasioukhin
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Immune Modulation ◽  
Large Scale ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Prostate Tumors ◽  
Structural Genomic ◽  
Primary Tumors ◽  
Recent Advances

Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes (ERG, PTEN, and SPOP) are recurrently mutated in more than 10% of primary tumors. On the other hand, metastatic castration-resistant tumors have more mutations, but, with the exception of the androgen receptor gene (AR), no single gene is altered in more than half of tumors. Structural genomic rearrangements are common, including ERG fusions, copy gains involving the MYC locus, and copy losses containing PTEN. Overall, instead of being associated with a single dominant driver event, prostate tumors display various combinations of modifications in oncogenes and tumor suppressors. This review takes a broad look at the recent advances in PCa research, including understanding the genetic alterations that drive the disease and how specific mutations can sensitize tumors to potential therapies. We begin with an overview of the genomic landscape of primary and metastatic PCa, enabled by recent large-scale sequencing efforts. Advances in three-dimensional cell culture techniques and mouse models for PCa are also discussed, and particular emphasis is placed on the benefits of patient-derived xenograft models. We also review research into understanding how ETS fusions (in particular, TMPRSS2-ERG) and SPOP mutations contribute to tumor initiation. Next, we examine the recent findings on the prevalence of germline DNA repair mutations in about 12% of patients with metastatic disease and their potential benefit from the use of poly(ADP-ribose) polymerase (PARP) inhibitors and immune modulation. Lastly, we discuss the recent increased prevalence of AR-negative tumors (neuroendocrine and double-negative) and the current state of immunotherapy in PCa. AR remains the primary clinical target for PCa therapies; however, it does not act alone, and better understanding of supporting mutations may help guide the development of novel therapeutic strategies.

Abstract LB-005: Senescence reprogramming in primary tumors initiates prostate cancer metastases

2020 ◽  
Author(s):  
Ilaria Guccini ◽  
Ajinkya Revandkar ◽  
Mariantonietta D'Ambrosio ◽  
Manuel Colucci ◽  
Emiliano Pasquini ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Tumors ◽  
Cancer Metastases

scholarly journals Comparative genomic analysis of primary tumors and paired brain metastases in lung cancer patients by whole exome sequencing: a pilot study

Oncotarget ◽  
2020 ◽  
Vol 11 (50) ◽  
pp. 4648-4654
Author(s):  
Pascale Tomasini ◽  
Fabrice Barlesi ◽  
Sophie Gilles ◽  
Isabelle Nanni-Metellus ◽  
Riccardo Soffietti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pilot Study ◽  
Brain Metastases ◽  
Cancer Patients ◽  
Genomic Analysis ◽  
Comparative Genomic Analysis ◽  
Comparative Genomic ◽  
Primary Tumors ◽  
Lung Cancer Patients ◽  
Whole Exome

Clinically relevant genomic alterations identified by targeted exome sequencing in U.S. veterans with prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17599-e17599
Author(s):  
Eman Dadashian ◽  
Michael Nakazawa ◽  
Neil Rohit Parikh ◽  
Nathisha Kalpage ◽  
Nicholas George Nickols ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
General Population ◽  
Large Scale ◽  
Mapk Pathway ◽  
Clinical Care ◽  
Cancer Tissue ◽  
Precision Oncology ◽  
Genomic Alterations ◽  
Primary Tumors ◽  
Prostate Cancers

e17599 Background: Amongst male United States Veterans, prostate cancer accounts for one third of cancer diagnoses and is the second leading cause of cancer death. Prostate cancers in the Veteran population may have differing frequencies of clinically relevant genomic alterations than the general population owing to chemical exposures, military service, or other unknown factors. Veterans, however, have been underrepresented in large-scale prostate cancer sequencing cohorts to date. Methods: Archival or fresh prostate cancer tissue from Veterans cared for by our team within the VA Greater Los Angeles Healthcare System (a VA Prostate Cancer Center of Excellence) undergo targeted sequencing as part of routine clinical care through the VA Precision Oncology Program. Sequencing covers over 181 genes frequently mutated in cancers. Prostate cancers from 81 Veterans (76 primary tumors, 5 metastases) have been sequenced through the Personalis ACE CancerPlus platform. Results: 43% of Veterans had primary tumors with clinically relevant genomic alterations, including 6.2% with activating mutations in MAPK pathway members (KRAS, ERBB2, or BRAF), 3.7% with somatic mutations in DDR genes (BRCA2 or ATR), 7.3% with mutations in TP53 or RB1, 4.9% in APC, 1.2% in the WNT pathway (CTNNB1), 3.7% with mutations in the PI3K/AKT pathway (PIK3R1 or AKT1), 3.7% with PTEN deletions, and 22.2% had alterations involving an AR regulated gene (SLC45A3 or TMPRSS). Of the five metastatic tumors sequenced, one had a mutation in TP53 and another had an ETS gene fusion detected. Half of the Veterans who underwent tumor sequencing consented for screening for, or enrollment on, active clinical trials at VA Greater LA. Conclusions: Large-scale sequencing of prostate cancers within VA is feasible and may facilitate enrollment in precision oncology trials specifically designed for Veterans. These data suggest that clinically relevant genomic alterations within the primary tumors may differ between Veterans and the general population; larger data sets along with more robust sequencing platforms are required for clarification.

Gamma Knife surgery as sole treatment for multiple brain metastases: 2-center retrospective review of 1508 cases meeting the inclusion criteria of the JLGK0901 multi-institutional prospective study

2010 ◽  
Vol 113 (Special_Supplement) ◽  
pp. 48-52 ◽  
Author(s):  
Toru Serizawa ◽  
Masaaki Yamamoto ◽  
Yasunori Sato ◽  
Yoshinori Higuchi ◽  
Osamu Nagano ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Gamma Knife ◽  
Class Ii ◽  
Hazard Ratio ◽  
Gamma Knife Surgery ◽  
Inclusion Criteria ◽  
Primary Tumors ◽  
Poor Prognostic Factor ◽  
Group A ◽  
Group B

Object The authors retrospectively reviewed the results of Gamma Knife surgery (GKS) used as the sole treatment for brain metastases in patients who met the eligibility criteria for the ongoing JLGK0901 multi-institutional prospective trial. They also discuss the anticipated results of the JLGK0901 study. Methods Data from 1508 consecutive cases were analyzed. All of the patients were treated at the Gamma Knife House of Chiba Cardiovascular Center or the Mito Gamma House of Katsuta Hospital between 1998 and 2007 and met the following JLGK0901 inclusion criteria: 1) newly diagnosed brain metastases, 2) 1–10 brain lesions, 3) less than 10 cm3 volume of the largest tumor, 4) no more than 15 cm3 total tumor volume, 5) no findings of CSF dissemination, and 6) no impairment of activities of daily living (Karnofsky Performance Scale score < 70) due to extracranial disease. At the initial treatment, all visible lesions were irradiated with GKS without upfront whole-brain radiation therapy. Thereafter, gadolinium-enhanced MR imaging was performed every 2–3 months, and new distant lesions were appropriately retreated with GKS. Patients were divided into groups according to numbers of tumors: Group A, single lesions (565 cases); Group B, 2–4 tumors (577 cases); and Group C, 5–10 tumors (366 cases). The differences in overall survival (OS) were compared between groups. Results The median age of the patients was 66 years (range 19–96 years). There were 963 men and 545 women. The primary tumors were in the lung in 1114 patients, gastrointestinal tract in 179, breast in 105, urinary tract in 66, and other sites in 44. The overall mean survival time was 0.78 years (0.99 years for Group A, 0.68 years for Group B, and 0.62 years for Group C). The differences between Groups A and B (p < 0.0001) and between Groups B and C (p = 0.0312) were statistically significant. Multivariate analysis revealed significant prognostic factors for OS to be sex (poor prognostic factor: male, p < 0.0001), recursive partitioning analysis class (Class I vs Class II and Class II vs III, both p < 0.0001), primary site (lung vs breast, p = 0.0047), and number of tumors (Group A vs Group B, p < 0.0001). However, no statistically difference was detected between Groups B and C (p = 0.1027, hazard ratio 1.124, 95% CI 0.999–1.265). Conclusions The results of this retrospective analysis revealed an upper CI of 1.265 for the hazard ratio, which was lower than the 1.3 initially set by the JLGK0901 study. The JLGK0901 study is anticipated to show noninferiority of GKS as sole treatment for patients with 5–10 brain metastases compared with those with 2–4 in terms of OS.

Gamma Knife surgery for metastatic brain tumors

2008 ◽  
Vol 109 (Supplement) ◽  
pp. 118-121 ◽  
Author(s):  
Toru Serizawa ◽  
Masaaki Yamamoto ◽  
Osamu Nagano ◽  
Yoshinori Higuchi ◽  
Shinji Matsuda ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Gamma Knife ◽  
Patient Selection ◽  
Selection Criterion ◽  
Gamma Knife Surgery ◽  
Treatment Result ◽  
Karnofsky Performance Scale ◽  
Consecutive Series ◽  
Primary Tumors ◽  
Patient Selection Criterion

Object The authors compared results of Gamma Knife surgery (GKS) for brain metastases obtained at 2 institutions in Japan. Methods They analyzed a consecutive series of 2390 patients with brain metastases who underwent GKS from 1998 through 2005 in 2 institutes (1181 patients in Chiba; 1209 in Mito). In the 2 facilities, 1 neurosurgeon each was responsible for diagnosis, patient selection, GKS procedures, and follow-up (T.S. in Chiba, M.Y. in Mito). Even if tumor numbers exceeded 4, all visible lesions were irradiated with a total skull integral dose (TSID) of ≤ 10–12 J. No prophylactic whole-brain radiotherapy (WBRT) was applied. If new distant lesions were detected, salvage GKS was appropriately performed. Results The distributions of patient and treatment factors did not differ between institutes. The most common primary tumors were lung cancer (1572 patients), followed by gastrointestinal tract (316), breast (211), kidney (113), and other cancers (159). The median survival periods were 7.7 months in Chiba and 7.0 months in Mito (p = 0.0635). The significant poor prognostic factors for overall survival were active extracranial disease status, male sex, and low initial Karnofsky Performance Scale score on multivariate analysis (all p < 0.0001). The neurological survival rates at 1 year were 86.6% in Chiba and 84.2% in Mito (p = 0.3310). Conclusions This 2-institute study demonstrated no significant institutional differences in any of the treatment result items. Gamma Knife surgery for brain metastases without prophylactic WBRT prevents neurological death and allows a patient to maintain good brain condition. However, there is 1 important patient selection criterion: regardless of how many tumors there are, all lesions can be irradiated with a TSID of ≤12 J.

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