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在小鼠中的BRCA2 R3052Q变体的表征支持其作为低风险变体的功能影响

Arun Prakash Mishra¹, Suzanne Hartford^1,2, Rajani Kant Chittela^1,3

¹Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.

Cell death & disease

|November 19, 2023

概括

这种BRCA2 R3052Q变异,以前的意义不确定,作为一个低形态变异. 这意味着它部分失去功能,影响DNA修复,并增加对某些癌症疗法的敏感性.

科学领域:

遗传学是一个遗传学.
癌症生物学癌症生物学
分子瘤学分子瘤学

背景情况:

在BRCA2的致病变体显著提高乳腺癌和卵巢癌的风险.
数以千计的不确定意义的BRCA2变体 (VUS) 缺乏明确的疾病风险数据.
这种BRCA2 p.Arg3052Gln变异具有相互矛盾的临床解释.

研究的目的:

为了研究BRCA2 p.Arg3052Gln变异的体内和体外功能影响.
使用小鼠模型确定BRCA2 R3052Q变异的致病性.

主要方法:

创建一个表达BRCA2 R3052Q变异的敲入鼠标模型.
评估小鼠的生存能力,生育能力和一般的表型.
在体外分析胎儿肝细胞和纤维细胞的增殖,DNA修复 (RAD51焦点) 和基因组稳定性.
对PARP抑制剂 (olaparib) 的敏感性评估.

主要成果:

同卵性和半卵性突变小鼠是可行的和肥沃的,没有明显的表型.
胎儿肝细胞在体外增殖减少,对olaparib过敏.
纤维细胞在辐射后呈现了减少的RAD51焦点形成,并在米托米辛C治疗后增加了基因组不稳定性.
一部分R3052Q BRCA2蛋白错误地定位到细胞质中.

结论:

这种BRCA2 R3052Q变体表现出功能减弱,被归类为低形态变体.
这种变异影响了DNA修复机制和细胞对DNA破坏剂的反应.
这些发现有助于对BRCA2 VUS和个性化癌症风险评估的临床解释.

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