Polymorphisms in DNA mismatch repair pathway genes predict toxicity and response to cisplatin chemoradiation in head and neck squamous cell carcinoma patients

Nogueira, Guilherme; Costa, Ericka Francislaine Dias; Lopes‐Aguiar, Leisa; Lima, Tathiane Regine Penna; Visacri, Marília Berlofa; Pincinato, Eder de Carvalho; Lourenço, Gustavo Jacob; Calonga, Luciane; Mariano, Fernanda Viviane; Altemani, Albina; Altemani, João Maurício Carrasco; Moriel, Patrícia; Chone, Carlos Takahiro; Ramos, Celso Darío; Lima, Carmen Sílvia Passos

doi:10.18632/oncotarget.25268

Cited by 28 publications

(54 citation statements)

References 45 publications

(54 reference statements)

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“…Zhu et al [27] recently observed that the rs2303428 genotype was an independent prognostic factor in hepatocellular carcinoma. Two other studies, however, failed to show an association of this polymorphism with prognosis and/or chemoradiotherapy response in rectal cancer and head and neck squamous cell carcinoma [28,29]. Together with our results relating its positive correlation with GC outcome, these findings may indicate a tumor type-dependent effect for this polymorphism.…”

Section: Discussionsupporting

confidence: 78%

“…Furthermore, some genetic defects may impact MMR function or activity other than MMR protein expression level [15]. Specifically, common polymorphisms of MMR genes with a low-penetrant effect that may be also insufficient to induce MSI can cause heterogeneous MMR capability among individuals, which correlates with cancer risk and clinical outcome [16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

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A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer

Zhao

Dai

et al. 2019

Gastric Cancer

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Background Defective mismatch repair (dMMR) and microsatellite instability (MSI) correlate with gastric cancer (GC) outcome. We hypothesized that MMR genetic polymorphisms that have low-penetrant effects but may cause heterogeneous MMR capability among individuals also affect GC outcome. Methods The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. Results In both the discovery and validation sets, the rs2303428 TC + CC genotype correlated with poor overall survival (OS) in non-cardia (P < 0.05) but not in cardia GC. Multivariate models showed that for OS of patients with non-cardia GC, the rs2303428 TC + CC genotype was an independent predictor in the validation set (HR 1.54; 95% CI 1.02-2.32; P = 0.040) and had a trend to be an independent predictor in the discovery set (HR 1.70; 95% CI 0.96-3.01; P = 0.067). Furthermore, in both patient sets, fluoropyrimidines-based adjuvant chemotherapy improved OS for non-cardia patients with the rs2303428 TC + CC genotype (HR 0.14; 95% CI 0.04-0.57; P = 0.006; and HR 0.29; 95% CI 0.15-0.58; P < 0.001, respectively) but not for those with the TT genotype. The rs2303428 genotypes were not associated with MSI frequency. The rs2303428 TC + CC genotype correlated with reduced expressions for thymidylate synthetase, P-glycoprotein and ERCC1 (P < 0.05) in non-cardia GC. Conclusions The rs2303428 genotypes may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer

Zhao

Dai

et al. 2019

Gastric Cancer

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“…37 MSH3 GG or GA and GT haplotype of EXO1 rs1047840 and rs9350 SNPs predisposed patients to significantly greater probability of pronounced ototoxicity from cisplatin than MSH3 AA genotype and other EXO1 haplotypes, respectively. 32 Genetic changes associated with better hearing outcomes have also been reported. Genes and SNPs related to protection against cisplatin ototoxicity include GSTM3 (rs1799735), GSTM1 null, GSTP (rs1695), SLC16A5 (rs4788863), OTOS (rs77124181; rs2291767), and OCT2 (rs316019).…”

Section: Pharmacogenomicsmentioning

confidence: 99%

“…Risk factors include young age (children under 5 years of age), 27,28 male children, 29 elderly patients, cumulative dose > 400 mg/m, 2,27 noise exposure, 30 combination with other ototoxic drugs 31 including carboplatin, 32 nutritional depletion and anemia, 33 cranial irradiation, 31 and genetic predisposition (pharmacogenomics).…”

Section: Risk Factors For Ototoxicitymentioning

confidence: 99%

Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

2019

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Cisplatin is a highly effective antineoplastic agent used to treat solid tumors. Unfortunately, the administration of this drug leads to significant side effects, including ototoxicity, nephrotoxicity, and neurotoxicity. This review addresses the mechanisms of cisplatin-induced ototoxicity and various strategies tested to prevent this distressing adverse effect. The molecular pathways underlying cisplatin ototoxicity are still being investigated. Cisplatin enters targeted cells in the cochlea through the action of several transporters. Once it enters the cochlea, cisplatin is retained for months to years. It can cause DNA damage, inhibit protein synthesis, and generate reactive oxygen species that can lead to inflammation and apoptosis of outer hair cells, resulting in permanent hearing loss. Strategies to prevent cisplatin ototoxicity have utilized antioxidants, transport inhibitors, G-protein receptor agonists, and anti-inflammatory agents. There are no FDA-approved drugs to prevent cisplatin ototoxicity. It is critical that potential protective agents do not interfere with the antitumor efficacy of cisplatin.

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“…The p.E216K mutation in POLB does not alter polymerase activity in vitro [15], but it has cellular effects in vivo (manuscript in preparation). The p.E589K mutation in EXO1 has been reported to affect the response to cisplatin treatment in patients with head and neck tumors [34], and thus may also be functional. Furthermore, all tumors with a Gleason score >7 contained either the p.E216K POLB mutation or a prevalent missense mutation in EXO1 (p.E589K, p.V458M, or p.H354R).…”

Section: Discussionmentioning

confidence: 99%

Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

et al. 2020

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Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1,

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Polymorphisms in DNA mismatch repair pathway genes predict toxicity and response to cisplatin chemoradiation in head and neck squamous cell carcinoma patients

Cited by 28 publications

References 45 publications

A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer

A polymorphism within the mismatch repair gene predicts prognosis and adjuvant chemotherapy benefit in gastric cancer

Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

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