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标题：Proteins with Evolutionarily Hypervariable Domains are Associated with Immune Response and Better Survival of Basal-like Breast Cancer Patients
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作者：Shutan Xu ; Yuan Feng ; Shaying Zhao 等
期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2019
卷号：17
页码：430-440
DOI：10.1016/j.csbj.2019.03.008
出版社：Computational and Structural Biotechnology Journal
摘要：Maltase-glucoamylase (MGAM) and MGAM2 both belong to the glycoside hydrolase family 31. MGAM, a therapeutic target for type 2 diabetes, is α-1,4-glucosidase and expressed in the intestine to catalyze starch digestion. MGAM2, however, is largely uncharacterized. By investigating The Cancer Genome Atlas data, we found that among breast cancer subtypes, MGAM2expression is nearly exclusive to basal-like breast cancers (BLBCs), whereas MGAMtends to express in luminal A breast cancers. Moreover, MGAM2expression is associated with better patient survival and correlated with immune genes/signatures, unlike MGAM. Both genes have emerged in mammals, but diverged after the placental-marsupial split. In placentals, MGAM2 has likely lost its α-1,4-glucosidase activity due to mutations in key catalytic sites, and has acquired a large domain that is extracellular, threonine-rich and evolutionarily hypervariable (EHV). Guided by MGAM2 findings, our genome-wide search identified >1000 human proteins with EHV regions. These proteins are enriched in immune functions and molecules, including major histocompatibility complex proteins. Their genes are expressed higher in BLBCs and are associated with better patient survival, like MGAM2. Their EHV-coding sequences are rich in simple repeats and harbor more cancer passenger mutations. In conclusion, MGAM2 diverges from MGAM structurally and likely functionally in placentals. MGAM2 is among >1000 human proteins with EHV regions and associated with immune response. We propose that these EHV molecules may have significant implication in cancer immunotherapy and BLBC treatment.
关键词：MGAM2 ; MGAM ; BLBC ; α-1;4-glucosidase ; EHV ; Immune response ; Patient survival ; Placental-marsupial split