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Aberrations of DNA Repair Pathways in Prostate Cancer 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 10735

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Special Issue Editor

Dr. Stergios Boussios

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Guest Editor

1. Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, London SE1 9RT, UK
2. Medway NHS Foundation Trust, Windmill Road, Kent, Gillingham ME7 5NY, UK
3. Kent Medway Medical School, University of Kent, Kent , Canterbury CT2 7LX, UK
4. AELIA Organization, 9(th)Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
Interests: prostate cancer; renal cancer; ovarian cancer; homologous recombination of DNA; PARP inhibitors; cervical cancer; carcinoma of unknown primary; colorectal cancer; cancer and autoimmune diseases; biomarkers
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Special Issue Information

Dear Colleagues,

Prostate cancer is the second most common neoplasm in men worldwide and the second leading cause of cancer deaths in Western countries. Due to the large-scale sequencing efforts, there is a better understanding of the genomic landscape of prostate cancer. Within this context, recurrent somatic mutations, copy number alterations, and oncogenic structural DNA rearrangements have been identified. These include point mutations in SPOP, FOXA1, and TP53; copy number alterations involving MYC, RB1, PTEN, and CHD1; and E26 transformation-specific (ETS) fusions. Data on mechanisms of DNA repair and experimental evidence still represent an urgent need. The identification of genomic defects in DNA repair has already led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients.

Carriers of BRCA2 pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and a high recurrence rate. BRCA2 PSVs confer lower overall survival. The association of BRCA1 and prostate cancer has not been replicated in all studies. The National Comprehensive Cancer Network guidelines recommend that BRCA2 carriers should begin PSA screening at 45 years of age, while BRCA1 carriers should be advised to consider it. The IMPACT study evaluated a tailored prostate cancer screening in men with BRCA1/2 germline mutation and proposed annual PSA tests and a prostate biopsy if PSA >3 ng/mL.

In this editorial, we highlight the biology of deleterious inherited or acquired DNA repair pathway aberrations in prostate cancer. The manuscripts should be focused on but are not only limited to:

Prostate risk assessment in the era of next-generation sequencing;
Prognostic biomarkers in metastatic castration-resistant prostate cancer;
Molecular signatures in prostate cancer;
Aberrations of DNA repair pathways in prostate cancer;
Germline genetic variants in prostate cancer;
PARP inhibitors in prostate cancer;
Targeting androgen receptor activity in prostate cancer;
Resistance to androgen receptor targeting therapies in prostate cancer;
Anti-angiogenesis in prostate cancer.

Dr. Stergios Boussios
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

prostate cancer
cancer screening
tumor microenvironment
molecular pathogenesis
biomarkers
liquid biopsies
PSA
androgens
androgen receptor
castration resistance
precision medicine

Published Papers (4 papers)

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Research

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13 pages, 864 KiB

Open AccessArticle

Impact of Somatic DNA Repair Mutations on the Clinical Outcomes of Bone Metastases from Castration-Resistant Prostate Cancer

by Maria Concetta Cursano, Emilio Francesco Giunta, Emanuela Scarpi, Chiara Casadei, Alessandra Virga, Paola Ulivi, Sara Bleve, Nicole Brighi, Giorgia Ravaglia, Francesco Pantano, Vincenza Conteduca, Daniele Santini and Ugo De Giorgi

Int. J. Mol. Sci. 2023, 24(15), 12436; https://doi.org/10.3390/ijms241512436 - 4 Aug 2023

Viewed by 3847

Abstract

Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne^® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume (p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer 2.0)

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Review

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26 pages, 2373 KiB

Open AccessReview

DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology

by Ioanna-Maria Grypari, Vasiliki Tzelepi and Kostis Gyftopoulos

Int. J. Mol. Sci. 2023, 24(14), 11418; https://doi.org/10.3390/ijms241411418 - 13 Jul 2023

Cited by 2 | Viewed by 2575

Abstract

Prostate cancer (PCa) has a distinct molecular signature, including characteristic chromosomal translocations, gene deletions and defective DNA damage repair mechanisms. One crucial pathway involved is homologous recombination deficiency (HRD) and it is found in almost 20% of metastatic castrate-resistant PCa (mCRPC). Inherited/germline mutations are associated with a hereditary predisposition to early PCa development and aggressive behavior. BRCA2, ATM and CHECK2 are the most frequently HRD-mutated genes. BRCA2-mutated tumors have unfavorable clinical and pathological characteristics, such as intraductal carcinoma. PARP inhibitors, due to the induction of synthetic lethality, have been therapeutically approved for mCRPC with HRD alterations. Mutations are detected in metastatic tissue, while a liquid biopsy is utilized during follow-up, recognizing acquired resistance mechanisms. The mismatch repair (MMR) pathway is another DNA repair mechanism implicated in carcinogenesis, although only 5% of metastatic PCa is affected. It is associated with aggressive disease. PD-1 inhibitors have been used in MMR-deficient tumors; thus, the MMR status should be tested in all metastatic PCa cases. A surrogate marker of defective DNA repair mechanisms is the tumor mutational burden. PDL-1 expression and intratumoral lymphocytes have ambivalent predictive value. Few experimental molecules have been so far proposed as potential biomarkers. Future research may further elucidate the role of DNA damage pathways in PCa, revealing new therapeutic targets and predictive biomarkers. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer 2.0)

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19 pages, 1034 KiB

Open AccessReview

Unravelling the Role of P300 and TMPRSS2 in Prostate Cancer: A Literature Review

by Charitomeni Gioukaki, Alexandros Georgiou, Lydia Evangelia Gkaralea, Christos Kroupis, Andreas C. Lazaris, Christos Alamanis and Georgia Eleni Thomopoulou

Int. J. Mol. Sci. 2023, 24(14), 11299; https://doi.org/10.3390/ijms241411299 - 11 Jul 2023

Cited by 2 | Viewed by 1754

Abstract

Prostate cancer is one of the most common malignant diseases in men, and it contributes significantly to the increased mortality rate in men worldwide. This study aimed to review the roles of p300 and TMPRSS2 (transmembrane protease, serine 2) in the AR (androgen receptor) pathway as they are closely related to the development and progression of prostate cancer. This paper represents a library-based study conducted by selecting the most suitable, up-to-date scientific published articles from online journals. We focused on articles that use similar techniques, particularly those that use prostate cancer cell lines and immunohistochemical staining to study the molecular impact of p300 and TMPRSS2 in prostate cancer specimens. The TMPRSS2:ERG fusion is considered relevant to prostate cancer, but its association with the development and progression as well as its clinical significance have not been fully elucidated. On the other hand, high p300 levels in prostate cancer biopsies predict larger tumor volumes, extraprostatic extension of disease, and seminal vesicle involvement at prostatectomy, and may be associated with prostate cancer progression after surgery. The inhibition of p300 has been shown to reduce the proliferation of prostate cancer cells with TMPRSS2:ETS (E26 transformation-specific) fusions, and combining p300 inhibitors with other targeted therapies may increase their efficacy. Overall, the interplay between the p300 and TMPRSS2 pathways is an active area of research. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer 2.0)

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15 pages, 861 KiB

Open AccessReview

From Biology to Diagnosis and Treatment: The Ariadne’s Thread in Cancer of Unknown Primary

by Beatrice Gadiel Mathew, Fine Aliyuda, Denis Taiwo, Kehinde Adekeye, Godwin Agada, Elisabet Sanchez, Aruni Ghose, Elie Rassy and Stergios Boussios

Int. J. Mol. Sci. 2023, 24(6), 5588; https://doi.org/10.3390/ijms24065588 - 15 Mar 2023

Cited by 5 | Viewed by 1964

Abstract

Cancer of unknown primary (CUP) encloses a group of heterogeneous tumours, the primary sites for which cannot be identified at the time of diagnosis, despite extensive investigations. CUP has always posed major challenges both in its diagnosis and management, leading to the hypothesis that it is rather a distinct entity with specific genetic and phenotypic aberrations, considering the regression or dormancy of the primary tumour; the development of early, uncommon systemic metastases; and the resistance to therapy. Patients with CUP account for 1–3% of all human malignancies and can be categorised into two prognostic subsets according to their clinicopathologic characteristics at presentation. The diagnosis of CUP mainly depends on the standard evaluation comprising a thorough medical history; complete physical examination; histopathologic morphology and algorithmic immunohistochemistry assessment; and CT scan of the chest, abdomen, and pelvis. However, physicians and patients do not fare well with these criteria and often perform additional time-consuming evaluations to identify the primary tumour site to guide treatment decisions. The development of molecularly guided diagnostic strategies has emerged to complement traditional procedures but has been disappointing thus far. In this review, we present the latest data on CUP regarding the biology, molecular profiling, classification, diagnostic workup, and treatment. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer 2.0)

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