scholarly journals Predictive Biomarkers of Dicycloplatin Resistance or Susceptibility in Prostate Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Minglu Liu ◽  
Xiaoyu Zhou ◽  
Jun Liu ◽  
Chelong Lu ◽  
Guoqing Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Somatic Mutations ◽  
Copy Number Variants ◽  
Predictive Biomarkers ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Group A ◽  
Resistant Group ◽  
Six Genes ◽  
Sensitive Group

BackgroundProstate cancer (PCa) is among the leading causes of cancer mortality. Dicycloplatin is a newer generation platinum-based drug that has less side effects than cisplatin and carboplatin. However, its effects in PCa is mixed due to lack of appropriate stratifying biomarkers. Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin.MethodsWe carried out whole-exome sequencing on cell-free DNA (cfDNA) and matched leukocyte DNA from 16 PCa patients before treatment with dicycloplatin. We then compared the clinical characteristics, somatic mutations, copy number variants (CNVs), and mutational signatures between the dicycloplatin-sensitive (nine patients) and dicycloplatin-resistant (seven patients) groups and tested the identified mutations, CNV, and their combinations as marker of dicycloplatin response.ResultsThe mutation frequency of seven genes (SP8, HNRNPCL1, FRG1, RBM25, MUC16, ASTE1, and TMBIM4) and CNV rate of four genes (CTAGE4, GAGE2E, GAGE2C, and HORMAD1) were higher in the resistant group than in the sensitive group, while the CNV rate in six genes (CDSN, DPCR1, MUC22, TMSB4Y, VARS, and HISTCH2AC) were lower in the resistant group than in the sensitive group. A combination of simultaneous mutation in two genes (SP8/HNRNPCL1 or SP8/FRG1) and deletion of GAGE2C together were found capable to predict dicycloplatin resistance with 100% sensitivity and 100% specificity.ConclusionWe successfully used cfDNA to monitor mutational profiles of PCa and designed an effective composite marker to select patients for dicycloplatin treatment based on their mutational profile.

scholarly journals Data on somatic mutations obtained by whole exome sequencing of FFPE tissue samples from Russian patients with prostate cancer

Data in Brief ◽  
2019 ◽  
Vol 25 ◽  
pp. 104022
Author(s):  
A.S. Nikitina ◽  
E.I. Sharova ◽  
S.A. Danilenko ◽  
O.V. Selezneva ◽  
L.O. Skorodumova ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Ffpe Tissue ◽  
Tissue Samples ◽  
Whole Exome

Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5072-5072
Author(s):  
Simon Yuen Fai Fu ◽  
Elie Ritch ◽  
Cameron Herberts ◽  
Steven Yip ◽  
Daniel Khalaf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Median Time ◽  
Somatic Mutation ◽  
Clinical Data ◽  
Castration Resistant Prostate Cancer ◽  
Control Cohort ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Mutation Burden ◽  
Homozygous Deletions

5072 Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA > 2% and were evaluable. 32 samples from 24 pts had > 11 mut/Mb and fell above the 95th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p < 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.

EPCO-03. GLIOMA ONCOGENESIS IN THE CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi1-vi2
Author(s):  
Léa Guerrini-Rousseau ◽  
Jane Merlevede ◽  
Philippe Denizeau ◽  
Felipe Andreiuolo ◽  
Pascale Varlet ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Somatic Mutations ◽  
Mismatch Repair Deficiency ◽  
Mutational Signatures ◽  
Tumor Mutation Burden ◽  
Repair Deficiency ◽  
Whole Exome ◽  
Mutation Burden ◽  
Tumor Material ◽  
Constitutional Mismatch Repair Deficiency

Abstract PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.

scholarly journals Somatic mutational profiles and germline polygenic risk scores in human cancer

2021 ◽  
Author(s):  
Yuxi Liu ◽  
Alexander Gusev ◽  
Yujing J. Heng ◽  
Ludmil B. Alexandrov ◽  
Peter Kraft
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Somatic Mutations ◽  
Human Cancer ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Age At Menarche ◽  
Polygenic Risk Score ◽  
Mutational Signatures ◽  
Polygenic Risk

ABSTRACTThe mutational profile of a cancer reflects the activity of the mutagenic processes which have been operative throughout the lineage of the cancer cell. These processes leave characteristic profiles of somatic mutations called mutational signatures. Mutational signatures, including single-based substitution (SBS) signatures, may reflect the effects of exogenous or endogenous exposures. Here, we used polygenic risk score (PRS) as proxies for exposures and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas project. We found 17 statistically significant associations after Bonferroni correction (p < 3.15×10−5), including positive associations between germline inflammatory bowel disease PRS and number of somatic mutations of signature SBS1 in prostate cancer and APOBEC-related signatures in breast cancer. The age at menarche PRS was inversely associated with mutation counts of SBS1 in prostate cancer. Our analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect mechanisms through hormone regulation and immunological responses that contribute to cancer etiology and drive cancer progression.

Rare Germline GLMN Variants Identified from Blue Rubber Bleb Nevus Syndrome Might Impact mTOR Signaling

2020 ◽  
Vol 22 (10) ◽  
pp. 675-682 ◽  
Author(s):  
Jie Yin ◽  
Zhongping Qin ◽  
Kai Wu ◽  
Yufei Zhu ◽  
Landian Hu ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Sanger Sequencing ◽  
Somatic Mutations ◽  
Venous Malformation ◽  
Underlying Disease ◽  
Mtor Signaling ◽  
Functional Effect ◽  
Germline Variants ◽  
Whole Exome

Backgrounds and Objective: Blue rubber bleb nevus syndrome (BRBN) or Bean syndrome is a rare Venous Malformation (VM)-associated disorder, which mostly affects the skin and gastrointestinal tract in early childhood. Somatic mutations in TEK have been identified from BRBN patients; however, the etiology of TEK mutation-negative patients of BRBN need further investigation. Method: Two unrelated sporadic BRBNs and one sporadic VM were firstly screened for any rare nonsilent mutation in TEK by Sanger sequencing and subsequently applied to whole-exome sequencing to identify underlying disease causative variants. Overexpression assay and immunoblotting were used to evaluate the functional effect of the candidate disease causative variants. Results: In the VM case, we identified the known causative somatic mutation in the TEK gene c.2740C>T (p.Leu914Phe). In the BRBN patients, we identified two rare germline variants in GLMN gene c.761C>G (p.Pro254Arg) and c.1630G>T(p.Glu544*). The GLMN-P254R-expressing and GLMN-E544X-expressing HUVECs exhibited increased phosphorylation of mTOR-Ser-2448 in comparison with GLMN-WTexpressing HUVECs in vitro. Conclusion: Our results demonstrated that rare germline variants in GLMN might contribute to the pathogenesis of BRBN. Moreover, abnormal mTOR signaling might be the pathogenesis mechanism underlying the dysfunction of GLMN protein.

scholarly journals Comparison of functional and oncological outcomes of innovative “three-port” and traditional “four-port” laparoscopic radical prostatectomy in patients with prostate cancer

BMC Urology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ben Xu ◽  
Si-da Cheng ◽  
Yi-ji Peng ◽  
Qian Zhang
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Biochemical Recurrence ◽  
Laparoscopic Radical Prostatectomy ◽  
Positive Surgical Margin ◽  
Oncological Outcomes ◽  
Estimated Blood Loss ◽  
Significant Difference ◽  
Group A ◽  
Group B

Abstract Background To compare the functional and oncological outcomes between innovative “three-port” and traditional “four-port” laparoscopic radical prostatectomy (LRP) in patients with prostate cancer (PCa). Methods We retrospectively collected the data of PCa patients treated at our institutions from June 2012 to May 2016. According to the inclusion criteria, a total of 234 patients were included in the study, including 112 in group A (four-port) and 122 in group B (three-port). The perioperatively surgical characteristics, functional and oncological outcomes were compared between groups. Results There were no statistical differences in the baseline parameters between these two groups. Compared with group A, the operative time (OT) and estimated blood loss (EBL) were significantly less in group B. On follow-up, the rate of positive surgical margin (PSM), prostate specific antigen (PSA) biochemical recurrence and continence after LRP did not show any statistically significant difference between the groups. An identical conclusion was also received in comparison of overall survival (OS) and biochemical recurrence-free survival (BRFS) between both groups. Conclusions Innovative “three-port” LRP can significantly shorten the OT and reduce the EBL compared with the traditional “four-port” LRP. Meanwhile, it does not increase the rate of PSM and PSA biochemical recurrence. “Three-port” LRP could be popularized in the future in view of its superior surgical technique, considerably better functional outcomes and remarkable oncological control.

scholarly journals Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuan Zong ◽  
Ying Zhang ◽  
Xinxin Peng ◽  
Dongyan Cao ◽  
Mei Yu ◽  
...  
Keyword(s):  
Copy Number Alteration ◽  
Germ Cell Tumors ◽  
Gonadal Development ◽  
Yolk Sac ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Yolk Sac Tumors ◽  
Molecular Aberrations

AbstractYolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.

scholarly journals Germline and somatic mutations in the pathology of pineal cyst: A whole‐exome sequencing study of 93 individuals

2021 ◽  
Author(s):  
Yuanqing Yan ◽  
Rebecca Martinez ◽  
Maria N. Rasheed ◽  
Joshua Cahal ◽  
Zhen Xu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Pineal Cyst ◽  
Whole Exome
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