Cancer in the Immunosuppressed Host

免疫抑制宿主的癌症

• 批准号: 9768990
• 负责人: J. Lee Nelson
• 金额: $ 8.36万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768990
• 关键词: Address; Adult; Aging; Allogenic; Biological; Biological Assay; Blood specimen; Canis familiaris; Carcinoma; Case Study; Cells; Child; Chronic; DNA; Family member; Female; Fetus; Fluorescent in Situ Hybridization; Genetic Polymorphism; Genotype; Health; Health Benefit; Heart Transplantation; Homologous Transplantation; Human; Immunocompromised Host; Immunohistochemistry; Immunosuppression; Individual; Kidney Transplantation; Lead; Life; Malignant Neoplasms; Mothers; Organ Donor; Organ Transplantation; Patients; Persons; Phenotype; Phenotypic Sex; Pregnancy; Recurrence; Reporting; Research Design; Resected; SNP array; Source; Specimen; Squamous Cell; Squamous cell carcinoma; Swab; Testing; Transplant Recipients; Woman; X Chromosome; Y Chromosome; design; experimental study; fetus cell; human leukocyte antigen testing; keratinocyte; male; mortality; offspring; peripheral blood; pregnant; recruit; residence; sex; tumor

PROJECT SUMMARY/ABSTRACT Cells exchanged between a mother and fetus during pregnancy are now known to establish long-term residence in the other individual creating a legacy of maternal cells in her progeny and cells of fetal origin in women who have been pregnant. The capacity for these naturally acquired cells to confer health benefits is supported by experimental and human studies. However detrimental effects on health may also sometimes occur. Transmissible cancer has been reported in dogs, Tasmanian devils, and in case reports in humans, primarily as mother to offspring transfer. To our knowledge no prior study has asked or addressed the possibility that naturally acquired allogeneic cells could sometimes be the source of a malignancy. Asking when this might occur led to this proposal. Patients who undergo organ transplantation are subject to long-term chronic immune suppression. Organ transplant recipients (OTR) are afflicted by multiple, frequently arising, squamous cell keratinocyte carcinomas (SCC). Recurrence rates and mortality related to SCC are significantly increased compared to non-immunosuppressed individuals. The purpose of this R03 application is to investigate SCC in OTR for allogeneic DNA and cells. Aim 1 will begin by interrogating DNA extracted from OTR SCCs by quantitative PCR (qPCR) for a Y-chromosome specific sequence; disproportionate absence of male DNA in tumors from males or presence of male DNA in tumors from females will be considered potential evidence for allogeneic cancer. Cellular studies will next be done by combined fluorescence in situ hybridization (FISH) with Y- and X-chromosome specific probes and concomitant immunohistochemistry (IHC) to identify, quantify, and phenotype sex-mismatched cells in tumor specimens. Aim 2 will investigate OTR SCCs to determine the specific origin of allogeneic DNA and cells detected in Aim 1. In part 1 of Aim 2 family members will be recruited so HLA and other polymorphism genotyping can be conducted. Results will be evaluated to identify a non-shared HLA (or other) polymorphism unique to the family member. DNA extracted from the tumor specimen will be quantitatively interrogated for the non-shared polymorphism selecting from a panel of HLA- and other polymorphism-specific qPCR assays we have developed for this purpose. qPCR testing will include an assay to detect donor origin DNA in tumors. For patients for whom family members are not available, Aim 2 part 2 will conduct SNP arrays and analysis of paired tumor and peripheral blood samples to determine whether tumor DNA is autochthonous or allogeneic in origin.

项目摘要/摘要 现在已知在怀孕期间在母亲和胎儿之间交换的细胞可以建立长期 居住在另一个人的居住在她的后代和胎儿起源细胞中的遗产 怀孕的妇女。这些自然获得的细胞赋予健康益处的能力是 得到实验和人类研究的支持。但是，对健康的有害影响有时也可能 发生。据报道，塔斯马尼亚魔鬼的可传染性癌症以及在人类的报告中， 主要是作为后代转移的母亲。据我们所知，没有事先研究已经询问或解决 自然获得的同种异体细胞有时可能是恶性肿瘤的根源。问 当这种情况发生时，这会导致此提案。进行器官移植的患者长期进行 慢性免疫抑制。器官移植受者（OTR）受多种，经常出现的折磨， 鳞状细胞角质形成癌（SCC）。与SCC相关的复发率和死亡率显着 与非免疫抑制的个体相比增加。此R03应用程序的目的是 研究同种异体DNA和细胞中OTR中的SCC。 AIM 1将首先询问从中提取的DNA 通过定量PCR（QPCR）进行Y染色体特异性序列的OTR SCC；不成比例的缺席 雄性的雄性DNA或女性肿瘤中雄性DNA的存在将被认为是潜在的 同种异体癌的证据。接下来，将通过荧光原位进行细胞研究 杂交（FISH）与Y-和X染色体特异性探针和伴随的免疫组织化学（IHC） 识别，量化和表型性不匹配的细胞中的肿瘤标本中的细胞。 AIM 2将调查OTR SCC确定AIM 1中检测到的同种异体DNA和细胞的特定起源。在AIM 2家族的第1部分 将招募成员，因此可以进行HLA和其他多态性基因分型。结果将是 评估以识别家庭成员独有的非共享HLA（或其他）多态性。 DNA提取 从肿瘤标本中，将对从A的非共享多态性进行定量询问 为此，我们开发的HLA-和其他多态性特异性QPCR分析。 qpcr 测试将包括检测肿瘤中供体起源DNA的测定法。对于家庭成员的患者 不可用，AIM 2第2部分将进行SNP阵列并分析配对的肿瘤和外周血样本 确定肿瘤DNA的起源是自chtothonos还是同种异体。