Biallelic tumour suppressor loss and DNA repair defects in <i>de novo</i> small‐cell prostate carcinoma

Chedgy, Edmund C.P.; Vandekerkhove, Gillian; Herberts, Cameron; Annala, Matti; Donoghue, Adam; Sigouros, Michael; Ritch, Elie; Struss, Werner J.; Konomura, Saki; Liew, Janet; Parimi, Sunil; Vergidis, Joanna; Hurtado-Coll, Antonio; Sboner, Andrea; Fazli, Ladan; Beltran, Himisha; N., Kim; Wyatt, Alexander W.

doi:10.1002/path.5137

Cited by 38 publications

(30 citation statements)

References 44 publications

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“…Blood and tissue processing were performed as previously described (Supplementary Methods) [10,14,15]. We employed an established targeted sequencing strategy capturing the exons of 73 PCa driver genes in cfDNA and tissue samples [10], modified by the inclusion of four bp molecular barcodes to the index sequence for cfDNA libraries.…”

Section: Sample Processing Dna Sequencing and Bioinformaticsmentioning

confidence: 99%

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

et al. 2019

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Word count abstract: 293Word count text: 2592 This is the accepted manuscript of the article, which has been published in European Urology. 2019, 75(4), 667-675. http://dx. AbstractBackground: Several systemic therapeutic options exist for metastatic castratesensitive prostate cancer (mCSPC). Circulating tumour DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer (mCRPC) and can influence decision-making, but remains untested in mCSPC. Objective:To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically-relevant information to a prostate biopsy. Design, Setting, and Participants:We collected plasma cell-free DNA (cfDNA) from 53 newly diagnosed patients with mCSPC and, where possible, during treatment.Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue. Results and Limitations:Median ctDNA fraction was 11% (range 0-84) among untreated patients but lower (1.0%, range 0-51) in patients after short term (median 22 days) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. Concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either are suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should ! 3 utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically-relevant somatic alterations in all patients. Patient summary:In men with advanced prostate cancer, tumour DNA shed into the bloodstream can be measured by a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies.! 4

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Section: Sample Processing Dna Sequencing and Bioinformaticsmentioning

confidence: 99%

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

et al. 2019

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“…It is not yet clear if primary NEPC and treatment‐induced small‐cell neuroendocrine prostate cancer (T‐SCNC) represent the same disease entity . However, a recent study suggested that primary small‐cell prostate cancer shared similar characteristics with T‐SCNC at the DNA and RNA levels, suggesting that the study of primary NEPC may provide clues relevant to T‐SCNC.…”

Section: Introductionmentioning

confidence: 99%

Low‐serum prostate‐specific antigen level predicts poor outcomes in patients with primary neuroendocrine prostate cancer

Wang

Abudurexiti

et al. 2019

The Prostate

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Background The rarities of primary neuroendocrine prostate cancer (NEPC) and primary adenocarcinoma with neuroendocrine differentiation (NE differentiation) mean that their clinical characteristics have not been fully elucidated. Materials and Methods A total of 449 patients with NEPC, including 352 cases of pure NEPC and 97 cases of NE differentiation, together with 408 629 cases of prostate adenocarcinoma at diagnosis were retrieved from the Surveillance, Epidemiology, and End Results program (2010‐2015). Clinical parameters and prognoses were compared between patients with different histological types of NEPC using the χ2 test and Kaplan‐Meier analysis, respectively. The prognostic value of prostate‐specific antigen (PSA) in NEPC and adenocarcinoma was evaluated using Cox regression and the Kaplan‐Meier method. Results Pure NEPC had higher rates of visceral metastases (brain, lung, and liver: 4.58%, 26.72%, and 36.64%, respectively) but a lower rate of bone metastasis (65.65%) compared with NE differentiation and prostate adenocarcinoma. Moreover, patients diagnosed with pure NEPC had a poorer outcome (median survival time: 10 months) compared with patients with NE differentiation (26 months) and prostate adenocarcinoma (median survival time not reached). Using PSA 4.1 to 10 ng/mL as the reference, the adjusted hazard ratios (HRs) for PSA lower than or equal to 4.0 ng/mL were 2.24 (95% confidence interval [CI]: 1.11‐4.55, P = .025) in the NE differentiation group and 1.57 (95% CI: 1.11‐2.23, P = .011) in the pure NEPC group. Conclusions Patients with NE differentiation had different clinical characteristics and a better prognosis than patients with pure NEPC. In addition, low‐serum PSA levels were associated with a poorer prognosis in patients with either NEPC or NE differentiation.

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“…The clinical sequence studies reveal that the germline BRCA2 mutation is detected in ∼5% of metastatic prostate carcinoma cases (91)(92)(93). Histologically, BRCA2-mutated prostate carcinoma is associated with high grade histology (94,95), including ductal (96) and endocrine (97,98) differentiation. On the other hand, pancreatic cancer also harbors BRCA2 mutations.…”

Section: Characteristics Of Cancer With Brca Dysfunctionsmentioning

confidence: 99%

Molecular Trajectory of BRCA1 and BRCA2 Mutations

et al. 2020

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Every cancer carries genomic mutations. Although almost all these mutations arise after fertilization, a minimal count of cancer predisposition mutations are already present at the time of genesis of germ cells. Of the cancer predisposition genes identified to date, BRCA1 and BRCA2 have been determined to be associated with hereditary breast and ovarian cancer syndrome. Such cancer predisposition genes have recently been attracting attention owing to the emergence of molecular genetics, thus, affecting the strategy of cancer prevention, diagnostics, and therapeutics. In this review, we summarize the molecular significance of these two BRCA genes. First, we provide a brief history of BRCA1 and BRCA2, including their identification as cancer predisposition genes and recognition as members in the Fanconi anemia pathway. Next, we describe the molecular function and interaction of BRCA proteins, and thereafter, describe the patterns of BRCA dysfunction. Subsequently, we present emerging evidence on mutational signatures to determine the effects of BRCA disorders on the mutational process in cancer cells. Currently, BRCA genes serve as principal targets for clinical molecular oncology, be they germline or sporadic mutations. Moreover, comprehensive cancer genome analyses enable us to not only recognize the current status of the known cancer driver gene mutations but also divulge the past mutational processes and predict the future biological behavior of cancer through the molecular trajectory of genomic alterations.

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Biallelic tumour suppressor loss and DNA repair defects in de novo small‐cell prostate carcinoma

Cited by 38 publications

References 44 publications

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

Low‐serum prostate‐specific antigen level predicts poor outcomes in patients with primary neuroendocrine prostate cancer

Molecular Trajectory of BRCA1 and BRCA2 Mutations

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