Radiation Resistance in Glioma Cells Determined by DNA Damage Repair Activity of Ape1/Ref-1

AbstractGastric cancer (GC) is highly heterogeneous in the stromal and immune microenvironment, genome instability (GI), and oncogenic signatures. However, a classification of GC by combining these features remains lacking. Using the consensus clustering algorithm, we clustered GCs based on the activities of 15 pathways associated with immune, DNA repair, oncogenic, and stromal signatures in three GC datasets. We identified three GC subtypes: immunity-deprived (ImD), stroma-enriched (StE), and immunity-enriched (ImE). ImD showed low immune infiltration, high DNA damage repair activity, high tumor aneuploidy level, high intratumor heterogeneity (ITH), and frequent TP53 mutations. StE displayed high stromal signatures, low DNA damage repair activity, genomic stability, low ITH, and poor prognosis. ImE had strong immune infiltration, high DNA damage repair activity, high tumor mutation burden, prevalence of microsatellite instability, frequent ARID1A mutations, elevated PD-L1 expression, and favorable prognosis. Based on the expression levels of four genes (TAP2, SERPINB5, LTBP1, and LAMC1) in immune, DNA repair, oncogenic, and stromal pathways, we developed a prognostic model (IDOScore). The IDOScore was an adverse prognostic factor and correlated inversely with immunotherapy response in cancer. Our identification of new GC subtypes provides novel insights into tumor biology and has potential clinical implications for the management of GCs.

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Re: Akt-Mediated Phosphorylation of Bmi1 Modulates its Oncogenic Potential, E3 Ligase Activity, and DNA Damage Repair Activity in Mouse Prostate Cancer

The Journal of Urology ◽

10.1016/j.juro.2012.10.108 ◽

2013 ◽

Vol 189 (2) ◽

pp. 771-771 ◽

Cited By ~ 1

Author(s):

Anthony Atala

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Repair ◽

E3 Ligase ◽

Oncogenic Potential ◽

Mouse Prostate ◽

Damage Repair ◽

Repair Activity

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Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

Cancers ◽

10.3390/cancers13143438 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3438

Author(s):

Liliana Raimundo ◽

Juliana Calheiros ◽

Lucília Saraiva

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Targeted Therapy ◽

Cancer Cells ◽

Synthetic Lethality ◽

Dna Damage Repair ◽

Driver Mutations ◽

Molecular Alterations ◽

Damage Repair ◽

Repair Activity

Precision medicine aims to identify specific molecular alterations, such as driver mutations, allowing tailored and effective anticancer therapies. Poly(ADP)-ribose polymerase inhibitors (PARPi) are the prototypical example of targeted therapy, exploiting the inability of cancer cells to repair DNA damage. Following the concept of synthetic lethality, PARPi have gained great relevance, particularly in BRCA1 dysfunctional cancer cells. In fact, BRCA1 mutations culminate in DNA repair defects that can render cancer cells more vulnerable to therapy. However, the efficacy of these drugs has been greatly affected by the occurrence of resistance due to multi-connected DNA repair pathways that may compensate for each other. Hence, the search for additional effective agents targeting DNA damage repair (DDR) is of crucial importance. In this context, BRCA1 has assumed a central role in developing drugs aimed at inhibiting DNA repair activity. Collectively, this review provides an in-depth understanding of the biology and regulatory mechanisms of DDR pathways, highlighting the potential of DDR-associated molecules, particularly BRCA1 and its interconnected partners, in precision cancer medicine. It also affords an overview about what we have achieved and a reflection on how much remains to be done in this field, further addressing encouraging clues for the advance of DDR targeted therapy.

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