DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy

Carignan, Damien; Lessard, Trystan; Villeneuve, Lyne; Desjardins, Sylvie; Magnan, Sindy; Després, Philippe; Martin, André‐Guy; Foster, William; Guillemette, Chantal; Lévesque, Éric; Vigneault, Éric

doi:10.1002/pros.23975

Cited by 4 publications

(3 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the close proximity to the tumor of the radiation source leads to reduced toxicity in healthy tissues [50]. It is likely that a different tumor response will be induced by brachytherapy compared to EBRT, in terms of induced DNA damage and activated DDR components [51,52]. This difference will be highly dependent on total applied dose and dose rate.…”

Section: Brachytherapymentioning

confidence: 99%

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Reuvers

Kanaar

Nonnekens

2020

Cancers

View full text Add to dashboard Cite

DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.

show abstract

Section: Brachytherapymentioning

confidence: 99%

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Reuvers

Kanaar

Nonnekens

2020

Cancers

View full text Add to dashboard Cite

show abstract

“…Numerous likely pathogenic/pathogenic loss of function (LoF) germline variants were observed in ERCC3 , with rs145201970 (n=42) representing the second most observed predicted LoF variant in this gene in cancer patients after rs34295337 (n=70) 26 . While there are no previous reports describing rs145201970 as a PrCa risk variant, an intronic ERCC3 variant has been previously associated with increased risk of biochemical recurrence after low-dose-rate prostate brachytherapy, potentially due to reduced mRNA expression in variant carriers 27 , while in breast cancer, a recurrent truncating mutation has been associated with familial disease 28,29 . In vitro studies have demonstrated mutations in ERCC3 impair DNA repair capability and confer a selective sensitivity to Irofulven, a sesquiterpene that has demonstrated some efficacy in clinical trials for metastatic PrCa 26 .…”

Section: Discussionmentioning

confidence: 99%

Germline sequencing of DNA-damage-repair genes in two hereditary prostate cancer cohorts reveals new disease risk-associated gene variants

Foley

Marthick

Lucas

et al. 2022

Preprint

View full text Add to dashboard Cite

BackgroundRare, inherited variants in DNA damage repair (DDR) genes play an important role in prostate cancer (PrCa) susceptibility.ObjectiveTo interrogate two independent high-risk familial PrCa datasets to identify rare DDR variants that contribute to disease risk.DesignMassively parallel sequencing data from Australian and North American familial PrCa datasets were examined for rare, likely deleterious variants in 35 DDR genes. Putative high-risk variants were prioritised based on frequency (minor allele frequency <1%), mutation type (nonsense, missense, or splice), segregation with disease, and in silico predicted deleteriousness. Six prioritised variants were genotyped in a total of 1,963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives and 322 screened controls) and MQLS association analysis performed.Results and LimitationsStatistically significant associations between PrCa risk and rare variants in ERCC3 (rs145201970, p=2.57×10−4) and BRIP1 (rs4988345, p=0.025) were identified in the combined Australian and North American datasets. A variant in PARP2 (rs200603922, p=0.028) was significantly associated with risk in the Australian dataset alone, while a variant in MUTYH (rs36053993, p=0.031) was significantly associated with risk in the North American dataset. Putative pathogenic variants may have been missed due to their very low frequency in the datasets, which precluded statistical evaluation.ConclusionsOur study implicates multiple rare germline DDR variants in PrCa risk, whose functional and/or biological effects and role in inherited risk in other PrCa cohorts should be evaluated. These findings will significantly impact the use of gene-based therapies targeting the DDR pathway in PrCa patients.Patient SummaryHere, we looked at genetic changes in a group of genes involved in DNA repair, as testing for such genetic changes is proving important in PrCa diagnosis and treatment. We report, for the first time, several new genetic changes in these genes associated with PrCa.

show abstract

“…[11] Several epidemiological studies have reported that alteration in specific genes (DNA repair pathways) can affect the repair activity, further affecting toxicity in prostate cancer patients. [13] MLH1 gene variant (rs1800734-93G > A) resulting in the substitution of Guanine with adenine is extensively studied in different population and be related to the increased susceptibility towards lung cancer, prostate, colorectal, and colon cancer and squamous cell carcinoma in different populations. [14][15][16][17] For MSH2 gene rs637499933 (Met688Arg, 2063 T > G), a missense mutation occurred due to T > G transition, leading to Methionine replacement by Arginine.…”

mentioning

confidence: 99%

Genetic polymorphisms in the mismatch repair pathway (MMR) genes contribute to hematological and gastrointestinal toxicity in North Indian lung cancer patients treated with platinum‐based chemotherapy

Singh

Sharma

2022

J Biochem & Molecular Tox

View full text Add to dashboard Cite

The present study investigated the relationship between MLH1, MSH2, MSH3, and MSH6 polymorphisms and toxicity due to platinum‐based doublet chemotherapy for North Indian lung cancer patients. Polymerase chain reaction‐restriction fragment length polymorphism technique was used to assess the polymorphism. For MSH2 IVS1 + 9G > C polymorphism variant type genotype reported a 1.4‐fold increased risk of anemia (AOR = 1.4; 95% CI = 0.98–1.99; p = 0.04) and decreased risk of developing gastrointestinal toxicity (diarrhea) (AOR = 0.53; 95% CI = 0.28–1.01; p = 0.04). Further, we also reported a 10‐fold increased risk of developing severe grade anorexia in combined genotype (GC + CC) (AOR = 9.18; 95% CI = 0.98–86.1; p = 0.05). For MSH2 T > C/‐6 polymorphism, variant type reported a 3‐fold and 2‐fold increased risk of developing severe grade leukopenia (AOR = 3.37; 95% CI = 1.44–7.88; p = 0.005) and neutropenia respectively (AOR = 2.23; 95% CI = 1.07–4.66; p = 0.03). For MSH3 G > A polymorphism, heterozygous (GA) and combined genotype (GA + AA) reported a 7‐fold and 6‐fold increased risk of developing anemia (AOR = 7.23; 95% CI = 1.51–34.6; p = 0.01, AOR = 6.39; 95% CI = 1.53–26.6; p = 0.01). Our results suggest that polymorphisms in DNA mismatch repair genes are associated with hematological, and gastrointestinal toxicities and might be considered a predictor for pretreatment evaluation in lung cancer patients.

show abstract

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy

Cited by 4 publications

References 27 publications

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Germline sequencing of DNA-damage-repair genes in two hereditary prostate cancer cohorts reveals new disease risk-associated gene variants

Genetic polymorphisms in the mismatch repair pathway (MMR) genes contribute to hematological and gastrointestinal toxicity in North Indian lung cancer patients treated with platinum‐based chemotherapy

Contact Info

Product

Resources

About