PDF(Pubmed)
Abstract：
DNA repair mechanisms are essential for tumorigenesis and disruption of HR mechanism is an important predisposing factor of human breast cancers (BC). PALB2 is an important part of the HR. There are similarities between canine mammary tumours (CMT) and BCs. As its human counterpart, PALB2 mutations could be a predisposing factor of CMT.
In this study, we aimed to investigate the impacts of PALB2 variants on tumorigenesis and canine mammary tumor (CMT) malignancy.
We performed Sanger sequencing to detect germline mutations in the WD40 domain of the canine PALB2 gene in CMT patients. We conducted in silico analysis to investigate the variants, and compared the germline PALB2 mutations in humans that cause breast cancer (BC) with the variants detected in dogs with CMT.
We identified an intronic (c.3096+8C>G) variant, two exonic (p.A1050V and p.R1354R) variants, and a 3\' UTR variant (c.4071T>C). Of these, p.R1354R and c.4071T>C novel variants were identified for the first time in this study. We found that the p.A1050V mutation had a significant effect. However, we could not determine sufficient similarity due to the differences in nucleotide/amino acid sequences between two species. Nonetheless, possible variants of human sequences in the exact location as their dog counterparts are associated with several cancer types, implying that the variants could be crucial for tumorigenesis in dogs. Our results did not show any effect of the variants on tumor malignancy.
The current project is the first study investigating the relationship between the PALB2 gene WD40 domain and CMTs. Our findings will contribute to a better understanding of the pathogenic mechanism of the PALB2 gene in CMTs. In humans, variant positions in canines have been linked to cancer-related phenotypes such as familial BC, endometrial tumor, and hereditary cancer predisposition syndrome. The results of bioinformatics analyses should be investigated through functional tests or case-control studies.
In this study, we aimed to investigate the impacts of PALB2 variants on tumorigenesis and canine mammary tumor (CMT) malignancy.
We performed Sanger sequencing to detect germline mutations in the WD40 domain of the canine PALB2 gene in CMT patients. We conducted in silico analysis to investigate the variants, and compared the germline PALB2 mutations in humans that cause breast cancer (BC) with the variants detected in dogs with CMT.
We identified an intronic (c.3096+8C>G) variant, two exonic (p.A1050V and p.R1354R) variants, and a 3\' UTR variant (c.4071T>C). Of these, p.R1354R and c.4071T>C novel variants were identified for the first time in this study. We found that the p.A1050V mutation had a significant effect. However, we could not determine sufficient similarity due to the differences in nucleotide/amino acid sequences between two species. Nonetheless, possible variants of human sequences in the exact location as their dog counterparts are associated with several cancer types, implying that the variants could be crucial for tumorigenesis in dogs. Our results did not show any effect of the variants on tumor malignancy.
The current project is the first study investigating the relationship between the PALB2 gene WD40 domain and CMTs. Our findings will contribute to a better understanding of the pathogenic mechanism of the PALB2 gene in CMTs. In humans, variant positions in canines have been linked to cancer-related phenotypes such as familial BC, endometrial tumor, and hereditary cancer predisposition syndrome. The results of bioinformatics analyses should be investigated through functional tests or case-control studies.
摘要：
背景：DNA修复机制对于肿瘤发生至关重要，HR机制的破坏是人类乳腺癌（BC）的重要诱发因素。PALB2是HR的重要组成部分。犬乳腺肿瘤（CMT）和BCs之间有相似之处。作为它的人类对应物，PALB2突变可能是CMT的易感因素。
目的：在本研究中，我们旨在研究PALB2变异体对肿瘤发生和犬乳腺肿瘤(CMT)恶性程度的影响.
方法：我们进行Sanger测序以检测CMT患者犬PALB2基因WD40结构域的种系突变。我们进行了硅分析以研究变体，并比较了导致乳腺癌（BC）的人类种系PALB2突变与CMT犬中检测到的变异。
结果：我们确定了一个内含子（c.30968C>G）变体，两个外显子（p。A1050V和p.R1354R)变体，和3'UTR变体（c.4071T>C）。其中,在本研究中首次鉴定出p.R1354R和c.4071T>C新变体。我们发现p.A1050V突变具有显著的效应。然而,由于两个物种之间核苷酸/氨基酸序列的差异，我们无法确定足够的相似性。尽管如此，人类序列在确切位置的可能变异，因为它们的狗对应物与几种癌症类型有关，这意味着这些变异可能对狗的肿瘤发生至关重要。我们的结果没有显示这些变体对肿瘤恶性肿瘤的任何影响。
结论：本项目是首次研究PALB2基因WD40结构域与CMT之间的关系。我们的发现将有助于更好地了解PALB2基因在CMT中的致病机制。在人类中,犬科动物的变异位置与癌症相关的表型，如家族性BC，子宫内膜肿瘤,和遗传性癌症易感性综合征.生物信息学分析的结果应通过功能测试或病例对照研究进行调查。
目的：在本研究中，我们旨在研究PALB2变异体对肿瘤发生和犬乳腺肿瘤(CMT)恶性程度的影响.
方法：我们进行Sanger测序以检测CMT患者犬PALB2基因WD40结构域的种系突变。我们进行了硅分析以研究变体，并比较了导致乳腺癌（BC）的人类种系PALB2突变与CMT犬中检测到的变异。
结果：我们确定了一个内含子（c.30968C>G）变体，两个外显子（p。A1050V和p.R1354R)变体，和3'UTR变体（c.4071T>C）。其中,在本研究中首次鉴定出p.R1354R和c.4071T>C新变体。我们发现p.A1050V突变具有显著的效应。然而,由于两个物种之间核苷酸/氨基酸序列的差异，我们无法确定足够的相似性。尽管如此，人类序列在确切位置的可能变异，因为它们的狗对应物与几种癌症类型有关，这意味着这些变异可能对狗的肿瘤发生至关重要。我们的结果没有显示这些变体对肿瘤恶性肿瘤的任何影响。
结论：本项目是首次研究PALB2基因WD40结构域与CMT之间的关系。我们的发现将有助于更好地了解PALB2基因在CMT中的致病机制。在人类中,犬科动物的变异位置与癌症相关的表型，如家族性BC，子宫内膜肿瘤,和遗传性癌症易感性综合征.生物信息学分析的结果应通过功能测试或病例对照研究进行调查。
