Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma,Cancer Genetics

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Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma
Cancer Genetics ( IF 1.9 ) Pub Date : 2023-05-20 , DOI: 10.1016/j.cancergen.2023.05.001
Aaron L Sarver ₁ , Lauren J Mills ₂ , Kelly M Makielski ₃ , Nuri A Temiz ₄ , Jinhua Wang ₄ , Logan G Spector ₅ , Subbaya Subramanian ₆ , Jaime F Modiano ₇

Affiliation

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN 55108, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Surgery, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN 55108, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA; Center for Engineering and Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

A hallmark of osteosarcoma in both human and canine tumors is somatic fragmentation and rearrangement of chromosome structure which leads to recurrent increases and decreases in DNA copy number. The PTEN gene has been implicated as an important tumor suppressor in osteosarcoma via forward genetic screens. Here, we analyzed copy number changes, promoter methylation and transcriptomes to better understand the role of PTEN in canine and human osteosarcoma. Reduction in PTEN copy number was observed in 23 of 95 (25%) of the canine tumors examined leading to corresponding decreases in PTEN transcript levels from RNA-Seq samples. Unexpectedly, canine tumors with an intact PTEN locus had higher levels of PTEN transcripts than human tumors. This variation in transcript abundance was used to evaluate the role of PTEN in osteosarcoma biology. Decreased PTEN copy number and transcript level was observed in - and likely an important driver of - increases in cell cycle transcripts in four independent canine transcriptional datasets. In human osteosarcoma, homozygous copy number loss was not observed, instead increased methylation of the PTEN promoter was associated with increased cell cycle transcripts. Somatic modification of PTEN, either by homozygous deletion in dogs or by promoter methylation in humans, is clinically relevant to osteosarcoma, because the cell cycle related transcripts are associated with patient outcomes. The PTEN gene is part of a syntenic rearrangement unique to the canine genome, making it susceptible to somatic loss of both copies of distal chromosome 26 which also includes the FAS death receptor.

Significance Statement

PTEN function is abrogated by different mechanisms in canine and human osteosarcoma tumors leading to uncontrolled cell cycling. Somatic loss of this canine specific syntenic region may help explain why the canine genome appears to be uniquely susceptible to osteosarcoma. Syntenic arrangement, in the context of copy number change, may lead to synergistic interactions that in turn modify species specific cancer risk. Comparative models of tumorigenesis may utilize different driver mechanisms.

中文翻译：

狗和人类 PTEN 失活的独特机制凸显了骨肉瘤发病机制中驱动细胞分裂的趋同分子事件

人类和犬类肿瘤中骨肉瘤的一个特点是体细胞断裂和染色体结构重排，导致 DNA 拷贝数反复增加和减少。通过正向遗传筛选， PTEN基因被认为是骨肉瘤中重要的肿瘤抑制因子。在这里，我们分析了拷贝数变化、启动子甲基化和转录组，以更好地了解PTEN在犬和人类骨肉瘤中的作用。在检查的 95 个犬肿瘤中，有 23 个 (25%) 观察到PTEN拷贝数减少，导致RNA-Seq 样本中PTEN转录物水平相应降低。出乎意料的是，具有完整PTEN基因座的犬肿瘤的PTEN转录物水平高于人类肿瘤。转录本丰度的这种变化用于评估PTEN在骨肉瘤生物学中的作用。在四个独立的犬类转录数据集中，观察到PTEN拷贝数和转录本水平下降，这可能是细胞周期转录本增加的重要驱动因素。在人骨肉瘤中，没有观察到纯合拷贝数丢失，相反，PTEN启动子甲基化的增加与细胞周期转录物的增加相关。PTEN的体细胞修饰（无论是通过狗的纯合缺失还是通过人类的启动子甲基化）在临床上与骨肉瘤相关，因为细胞周期相关转录本与患者的预后相关。PTEN基因是犬基因组特有的同线重排的一部分，使其容易受到 26 号远端染色体（也包括 FAS死亡受体）两个拷贝体细胞丢失的影响。