Nudelman Kelly, Nho Kwangsik, Zhang Michael, McDonald Brenna C, Zhai Wanting, Small Brent J, Wegel Claire E, Jacobsen Paul B, Jim Heather S L, Patel Sunita K, Graham Deena M A, Ahles Tim A, Root James C, Foroud Tatiana, Breen Elizabeth C, Carroll Judith E, Mandelblatt Jeanne S, Saykin Andrew J
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cancers (Basel). 2023 May 23;15(11):2877. doi: 10.3390/cancers15112877.
There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ ( = 325) and age-, racial/ethnic group-, and education-matched controls ( = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 ( gene ( = 1.624 × 10), and rs78786199 (chromosome 2, = 1.925 × 10) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.
目前尚未有关于癌症及治疗相关认知功能下降（CRCD）遗传学的全基因组研究发表；本研究的目的是在老年女性乳腺癌幸存者中识别与CRCD相关的基因变异。分析纳入了年龄在60岁及以上的非转移性乳腺癌白人非西班牙裔女性（n = 325）以及年龄、种族/族裔和教育程度匹配的对照组（n = 340），这些对照组在全身治疗前和一年随访时进行了认知评估。使用注意力、处理速度和执行功能（APE）以及学习和记忆（LM）的认知测试纵向领域得分来评估CRCD。一年认知的线性回归模型包括一个SNP或基因SNP富集*癌症病例/对照状态的交互项，同时控制人口统计学变量和基线认知。携带两个SNP（分别位于染色体1上的半腱蛋白1基因中的rs76859653，P = 1.624 × 10⁻⁵；以及位于染色体2上基因间区域的rs78786199，P = 1.925 × 10⁻⁵）次要等位基因的癌症患者，其一年的APE得分低于非携带者和对照组。基因水平分析显示，POC5中心粒蛋白基因富集了与患者和对照组纵向LM表现差异相关的SNP。与幸存者而非对照组认知相关的SNP是环核苷酸磷酸二酯酶家族的成员，该家族在细胞信号传导、癌症风险和神经退行性变中起重要作用。这些发现提供了初步证据，表明新的基因位点可能与CRCD易感性有关。
