对一个有非小细胞肺癌家族史的家庭中p.V1010M种系突变的系谱分析。
Pedigree analysis of the p.V1010M germline mutation in a family with a family history of non-small-cell lung cancer.
作者信息
Li Na, Liu Chunyi, Xiong Lan, Huang Depei, Jiang Youfan
机构信息
Department of Respiratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
The Medical Department, 3D Medicines Inc., Shanghai, China.
出版信息
Ann Transl Med. 2022 Feb;10(3):154. doi: 10.21037/atm-21-6925.
BACKGROUND
Tumors can be caused by genetic or environmental factors, but previous studies have shown that genetic factors contribute less to lung cancer than environmental factors. The epidermal growth factor receptor () is the most common driver gene in non-small-cell lung cancer (NSCLC), but most variations are somatic. In this study, we reported on the pedigree of the p.V1010M germline mutation for the first time, and explored the correlation between the V1010M and the occurrence of NSCLC. Further, the effect of the V1010M on the treatment of the EGFR-tyrosine kinase inhibitors (TKIs) was investigated through the treatment of the proband with the simultaneous somatic mutation of the p.L858R.
METHODS
The family members were screened using next-generation sequencing (NGS) and Sanger sequencing, and the pedigree was analyzed to examine the relationship between the p.V1010M and the occurrence of NSCLC. Schrodinger software was used to predict the structural function of the mutant amino acid sequence proteins.
RESULTS
A total of 10 blood samples were collected from 4 generations of family members, many of whom had suffered from lung cancer. Six carriers of the p.V1010M were detected. The pedigree analysis showed that there was still no evidence of a correlation between the p.V1010M and disease occurrence. Additionally, the proband had the p.L858R somatic mutation, and the response after the treatment of gifitinib was stable disease (SD), which turned to progressive disease (PD) some 4 months later. Schrodinger software showed that the 1010th amino acid valine was located near the C terminal, and the variation to methionine had little effect on the structure of the EGFR dimer.
CONCLUSIONS
This study is the first report on pedigree with the p.V1010M germline mutation. Further research needs to be conducted to determine whether this mutation is pathogenic, but it is likely related to EGFR-TKI resistance in NSCLC.
背景
肿瘤可由遗传或环境因素引起，但既往研究表明，遗传因素在肺癌发生中的作用小于环境因素。表皮生长因子受体（EGFR）是非小细胞肺癌（NSCLC）中最常见的驱动基因，但大多数变异是体细胞变异。在本研究中，我们首次报道了EGFR p.V1010M胚系突变的家系，并探讨了V1010M与NSCLC发生之间的相关性。此外，通过对携带EGFR p.L858R体细胞突变的先证者进行治疗，研究了V1010M对EGFR酪氨酸激酶抑制剂（TKIs）治疗效果的影响。
方法
使用二代测序（NGS）和桑格测序对家庭成员进行筛查，并分析家系以检查EGFR p.V1010M与NSCLC发生之间的关系。使用薛定谔软件预测突变氨基酸序列蛋白的结构功能。
结果
从4代家庭成员中总共采集了10份血样，其中许多人患有肺癌。检测到6名EGFR p.V1010M携带者。家系分析表明，仍没有证据表明EGFR p.V1010M与疾病发生之间存在相关性。此外，先证者具有EGFR p.L858R体细胞突变，吉非替尼治疗后的反应为疾病稳定（SD），约4个月后转为疾病进展（PD）。薛定谔软件显示，第1010位氨基酸缬氨酸位于C末端附近，突变为甲硫氨酸对EGFR二聚体的结构影响很小。
结论
本研究是关于EGFR p.V1010M胚系突变家系的首次报道。需要进一步研究以确定该突变是否具有致病性，但它可能与NSCLC中的EGFR-TKI耐药性有关。
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