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Genetic interactions between INPP4B and RAD50 is prognostic of breast cancer survival.

INPP4B 和 RAD50 之间的遗传相互作用是乳腺癌生存的预后。

  • 影响因子:2.87
  • DOI:10.1042/BSR20192546
  • 作者列表:"Chen X","Theobard R","Zhang J","Dai X
  • 发表时间:2020-01-31
Abstract

:RAD50 is commonly depleted in basal-like breast cancer with concomitant absence of INPP4B and several tumor suppressors such as BRCA1 and TP53. Our previous study revealed that INPP4B and RAD50 interact and such an interaction is associated with breast cancer survival at the transcriptional, translational and genomic levels. In the present study, we explored single nucleotide polymorphisms (SNPs) of these two genes that have synergistic effects on breast cancer survival to decipher mechanisms driving their interactions at the genetic level. The Cox's proportional hazards model was used to test whether SNPs of these two genes are interactively associated with breast cancer survival, following expression quantitative trait loci (eQTL) analysis and functional investigations. Our study revealed two disease-associating blocks, each encompassing five and two non-linkage disequilibrium linked SNPs of INPP4B and RAD50, respectively. Concomitant presence of any rare homozygote from each disease-associating block is synergistically prognostic of poor breast cancer survival. Such synergy is mediated via bypassing pathways controlling cell proliferation and DNA damage repair, which are represented by INPP4B and RAD50. Our study provided genetic evidence of interactions between INPP4B and RAD50, and deepened our understandings on the orchestrated genetic machinery governing tumor progression.

摘要

: RAD50 通常在基底样乳腺癌中耗竭,同时缺乏 INPP4B 和 BRCA1 和 tp53 等几种肿瘤抑制因子。我们之前的研究揭示了 INPP4B 和 RAD50 相互作用,这种相互作用在转录、翻译和基因组水平上与乳腺癌生存相关。在本研究中,我们探索了这两个对乳腺癌生存有协同作用的基因的单核苷酸多态性 (SNPs),以破译在遗传水平上驱动其相互作用的机制。在表达数量性状位点 (eQTL) 分析和功能研究后,使用 Cox 比例风险模型检验这两个基因的 SNPs 是否与乳腺癌生存交互相关。我们的研究揭示了两个疾病相关块,每个块分别包含 INPP4B 和 RAD50 的 5 个和 2 个非连锁不平衡连锁 SNPs。伴随存在来自每种疾病相关阻滞的任何罕见纯合子是乳腺癌生存率差的协同预后。这种协同作用是通过旁路控制细胞增殖和 DNA 损伤修复的途径介导的,以 INPP4B 和 rad50 为代表。我们的研究提供了 INPP4B 和 RAD50 之间相互作用的遗传学证据,加深了我们对控制肿瘤进展的精心策划的遗传机制的理解。

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影响因子:2.78
发表时间:2020-02-01
DOI:10.1007/s11010-019-03679-5
作者列表:["Singh N","Shaik FA","Myal Y","Chelikani P"]

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翻译标题与摘要 下载文献
影响因子:2.87
发表时间:2020-01-31
来源期刊:Bioscience reports
DOI:10.1042/BSR20192546
作者列表:["Chen X","Theobard R","Zhang J","Dai X"]

METHODS::RAD50 is commonly depleted in basal-like breast cancer with concomitant absence of INPP4B and several tumor suppressors such as BRCA1 and TP53. Our previous study revealed that INPP4B and RAD50 interact and such an interaction is associated with breast cancer survival at the transcriptional, translational and genomic levels. In the present study, we explored single nucleotide polymorphisms (SNPs) of these two genes that have synergistic effects on breast cancer survival to decipher mechanisms driving their interactions at the genetic level. The Cox's proportional hazards model was used to test whether SNPs of these two genes are interactively associated with breast cancer survival, following expression quantitative trait loci (eQTL) analysis and functional investigations. Our study revealed two disease-associating blocks, each encompassing five and two non-linkage disequilibrium linked SNPs of INPP4B and RAD50, respectively. Concomitant presence of any rare homozygote from each disease-associating block is synergistically prognostic of poor breast cancer survival. Such synergy is mediated via bypassing pathways controlling cell proliferation and DNA damage repair, which are represented by INPP4B and RAD50. Our study provided genetic evidence of interactions between INPP4B and RAD50, and deepened our understandings on the orchestrated genetic machinery governing tumor progression.

翻译标题与摘要 下载文献
影响因子:3.29
发表时间:2020-01-31
来源期刊:BMC cancer
DOI:10.1186/s12885-020-6534-z
作者列表:["Soliman H","Shah V","Srkalovic G","Mahtani R","Levine E","Mavromatis B","Srinivasiah J","Kassar M","Gabordi R","Qamar R","Untch S","Kling HM","Treece T","Audeh W"]

METHODS:BACKGROUND:Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS:IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS:The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS:The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION:"Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.

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