Research Unit of Medical Genetics, Department of Medicine, University Campus-Biomedico of Rome, Via Alvaro del Portillo 21, 00128 Roma, Italy.
Operative Research Unit of Medical Genetics, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo 200, 00128 Roma, Italy.
Genes (Basel). 2024 Apr 26;15(5):554. doi: 10.3390/genes15050554.
germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue.
we used Sanger sequencing and immunohistochemistry to search for a second variant in the tumoral DNA and to assess protein expression, respectively.
we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced.
our results fail to demonstrate that germinal monoallelic variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the protein in many tumors suggests its dysregulation regardless of genetic status.
在一些患有乳腺癌/卵巢癌或子宫内膜癌的患者中已经检测到种系单等位基因突变，这表明存在潜在的易感性作用，尽管由于疾病机制通常为隐性，其意义仍难以捉摸。因此，本研究旨在探讨假设，即在肿瘤组织中的另一个等位基因中可能已经出现了第二个打击。
我们分别使用 Sanger 测序和免疫组织化学来搜索肿瘤 DNA 中的第二个变体，并评估蛋白质表达。
我们检测到一个意义不明的变体，一个致病性有冲突解释的变体和三个良性/可能良性的变体；有一半的患者的肿瘤组织中未检测到该蛋白，而在其他患者中，其表达减少。
我们的结果未能证明种系单等位基因突变通过体细胞组织中的 LOH（杂合性丢失）机制增加癌症风险；然而，许多肿瘤中该蛋白的缺失或部分缺失表明其失调，无论遗传状态如何。
