Cancer in the Immunosuppressed Host

免疫抑制宿主的癌症

• 批准号: 10602868
• 负责人: J. Lee Nelson
• 金额: $ 0.44万
• 依托单位: FRED HUTCHINSON CANCER 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602868
• 关键词: Cancer; Immunosuppressed; Host

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，怀孕期间母亲和胎儿之间交换的细胞可以建立长期的 居住在另一个人身上，在她的后代中创造了母性细胞的遗产，并在 怀孕的女性。这些自然获得的细胞赋予健康益处的能力是 由实验和人体研究支持。然而，有时对健康的有害影响也可能 发生。在狗和塔斯马尼亚魔鬼中已有可传播癌症的报道，在人类中也有报道， 主要是作为母亲向后代的转移。据我们所知，没有任何先前的研究询问或解决过 自然获得的同种异体细胞有时可能是恶性肿瘤的来源。追问 当这种情况可能发生时，导致了这一提议。接受器官移植的患者要接受长期的 慢性免疫抑制。器官移植受者(OTR)患有多发性的、频繁的、 鳞状细胞角质形成细胞癌(SCC)。与鳞癌相关的复发率和死亡率显著 与非免疫抑制个体相比有所增加。此R03应用程序的目的是 研究OTR中同种异体DNA和细胞的SCC。目标1将首先审问从 通过定量聚合酶链式反应(QPCR)检测Y染色体特异序列；不成比例地缺乏 男性肿瘤中的男性DNA或女性肿瘤中的男性DNA将被认为是潜在的 同种异体癌症的证据。接下来，细胞研究将通过组合原位荧光进行。 Y、X染色体特异性探针杂交(FISH)及免疫组织化学(IHC) 对肿瘤标本中性别不匹配的细胞进行鉴定、量化和表型分析。AIM 2将调查OTR SCCS用于确定在AIM 1中检测到的同种异体DNA和细胞的特定来源。在AIM 2家族的第1部分 将招募成员，以便进行人类白细胞抗原和其他多态基因分型。结果将是 评估以识别家庭成员特有的非共享的人类白细胞抗原(或其他)多态。提取的DNA 将定量询问来自肿瘤样本的非共享多态性 为此目的，我们开发了一组人类白细胞抗原和其他多态特异的定量聚合酶链式反应方法。QPCR 测试将包括一种检测肿瘤中供体来源DNA的测试。为家庭成员所支持的患者 AIM 2第二部分将对配对的肿瘤和外周血液样本进行SNP阵列和分析 以确定肿瘤DNA来源是自体还是同种异体。