Hao Chunfang, Wang Chen, Lu Ning, Zhao Weipeng, Li Shufen, Zhang Li, Meng Wenjing, Wang Shuling, Tong Zhongsheng, Zeng Yanwu, Lu Leilei
Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Operations Department, Shanghai OrigiMed Co., Ltd., Shanghai, China.
Front Oncol. 2022 Apr 14;12:778511. doi: 10.3389/fonc.2022.778511. eCollection 2022.
Clinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics.
There were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher's exact test compared each pair of genes. A similarity score was constructed with the resulting -values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients.
Gene-by-gene analysis found that mutations were positively correlated with ER status while and mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 (, , , , and ) was significantly associated with PR status; gene cluster 2 (, , , , and ) and gene cluster 3 (, , , and ) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively.
This study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance.
雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子2（HER2）等临床特征是乳腺癌治疗中的重要生物标志物，但基因组突变如何影响其状态鲜有研究。本研究旨在寻找与这些临床特征相关的基因组突变。
本研究纳入了160例乳腺癌患者。采集这些患者的样本用于二代测序，靶向一组624个泛癌基因。鉴定每个样本中的短核苷酸突变、拷贝数变异和基因融合。采用Fisher精确检验比较每对基因。用所得P值构建相似性评分。根据相似性评分对基因进行聚类。根据患者的突变情况，将鉴定出的基因簇与ER、PR、HER2和癌症家族史（FH）等临床特征状态进行比较。
逐基因分析发现，[具体基因1]突变与ER状态呈正相关，而[具体基因2]和[具体基因3]突变与HER2状态呈正相关。基于突变的聚类鉴定出四个基因簇。基因簇1（[具体基因4]、[具体基因5]、[具体基因6]、[具体基因7]和[具体基因8]）与PR状态显著相关；基因簇2（[具体基因9]、[具体基因10]、[具体基因11]、[具体基因12]和[具体基因13]）和基因簇3（[具体基因14]、[具体基因15]、[具体基因16]和[具体基因17]）与ER状态显著相关；基因簇2也与癌症家族史呈负相关；基因簇4与年龄呈显著负相关。患者被分为四个相应的组。患者组1、2、3和4中分别有24.1%、36.5%、38.7%和41.3%的患者具有FDA认可的预测对FDA批准药物反应的生物标志物。
本研究鉴定出与ER和PR状态呈正相关的基因组突变。这些发现不仅揭示了维持ER和PR状态的候选基因，还为内分泌治疗耐药患者提供了潜在的治疗靶点。
