The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi's anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2, also known as FANCS and FANCD1, respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer.
Introduction Up to 15% cases of breast cancer are familial. However, the two most prevalent susceptibility genes, BRCA1 and BRCA2, only account for 25% of the familial cases. To this regard, we aimed to identify recurrent variants associated with familial breast cancer in Chaoshan Area of China by whole genome sequencing. Materials & Methods In the present study, Whole Genome Sequencing was performed in 8 familial breast cancer families with 13 familial breast cancer cases and 25 healthy relatives from Chaoshan Area. All the variants were filtered and prioritized by co-segregation analysis and bioinformatic tools. Results A total of 714 variants in 609 genes were selected as rare, probably damaging pathogenic mutations after co-segregation and functional prediction analysis in each family. In all the 609 genes, the zinc finger protein family was overlapped in all the 8 families, among which the c.120-130del of ZNF77 was overlapped in 3 families, c.279_791de of ZNF544 and c.T895A of ZNF479 in 2 families respectively, which emphasized the great significance of ZNF family in the mutational spectrum of Chaoshan Area. After that, the KEGG Pathway analysis in KOBAS 3.0 implied the significance of PI3K-Akt pathway in all the mutated 609 genes. At the same time, the PPI analysis by Cytoscape 3.6.1 indicated that all ZNF genes were interacted with one specific gene, PHLPP2, which inhibits the PI3K-Akt pathway similar to PTEN. Furthermore, two website-based bioinformatic tools cBioportal and Oncomine have predicted the positive correlations between ZNF77 and PHLPP2. All the analysis above was demonstrated the great significance of ZNFs-PHLPP2-AKT axis in the mutational spectrum of familial breast cancer of Chaoshan Area, in China. Conclusions Zinc finger protein family, especially ZNF77, are frequently mutated in the familial breast cancer of Chaoshan Area, which results in the down regulation of PHLPP2 and subsequently reverse the inhibition of PI3K-Akt pathway, and finally lead to tumorigenesis. Citation Format: Can-Bin Fang, Qian-Qian Ye, Jing Liu, Guo-Jun Zhang. Whole genome sequencing reveals a significant role of ZNFs-PHLPP2-AKT axis in familial breast cancer of chaoshan area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-302.
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