Institute of Science, Nirma University, Ahmadabad, Gujarat India.
Institute of Technology, Nirma University, Gujarat India.
Asian Pac J Cancer Prev. 2023 Jun 1;24(6):2129-2134. doi: 10.31557/APJCP.2023.24.6.2129.
The use of high-throughput genotyping techniques has enabled us to identify the rare germline genetic variants with different pathogenicity and penetrance, and understand their role in cancer predisposition. We report here a familial cancer case, a study from Western Indian.
NGS-WES was carried out in a lung cancer patient who has a family history of multiple cancers across generations, including tongue, lung, brain, cervical, urothelial, and esophageal cancer. The results were validated by data mining from available data bases. I-TASSER, RasMol and PyMol were used for protein structure modelling.
The sequencing by NGS-WES revealed PPM1D c.1654C>T (p.Arg552Ter) mutation in hotspot region exon 6 leading to sudden protein truncation and loss of the C-terminal, due to the substitution of C>T. This mutation was classified as a variant of uncertain significance (VUS), due to limited data on lung cancer, The three unaffected siblings of proband did not show any pathogenic variants and comparative analysis of the four siblings indicate 9 shared genetic variants, classified as benign as per ClinVar.
PPM1D constitutional genetic alterations are rare and uncommon in different ethnic populations. This gene encodes a phosphatase playing role in regulating the P53 tumor suppressor pathway and DNA damage response. Genetic alterations in the PPM1D gene maybe linked to history of gliomas, breast cancer, and ovarian cancer onset in the proband's family.
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高通量基因分型技术的应用使我们能够识别具有不同致病性和外显率的罕见种系遗传变异体，并了解它们在癌症易感性中的作用。我们在这里报告一个来自印度西部的家族性癌症病例研究。
对一名有跨代多种癌症家族史（包括舌、肺、脑、宫颈、尿路上皮和食管）的肺癌患者进行 NGS-WES 检测。结果通过挖掘现有数据库进行验证。使用 I-TASSER、RasMol 和 PyMol 进行蛋白质结构建模。
NGS-WES 测序显示 PPM1D c.1654C>T（p.Arg552Ter）突变位于热点区域外显子 6 中，导致 C>T 取代导致蛋白质截短和 C 端丢失。由于肺癌相关数据有限，该突变被归类为意义未明的变异体（VUS）。先证者的 3 名无血缘关系的兄弟姐妹均未显示任何致病性变异体，对 4 名兄弟姐妹的比较分析表明有 9 个共享的遗传变异体，根据 ClinVar 被归类为良性。
PPM1D 种系遗传改变在不同种族人群中罕见且不常见。该基因编码一种磷酸酶，在调节 P53 肿瘤抑制途径和 DNA 损伤反应中发挥作用。PPM1D 基因突变可能与先证者家族中的神经胶质瘤、乳腺癌和卵巢癌发病史有关。
