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.

项目总结/摘要 现在已知，在怀孕期间母亲和胎儿之间交换的细胞可以建立长期的 居住在另一个人创造了一个遗产的母体细胞在她的后代和细胞的胎儿来源， 已经怀孕的妇女。这些自然获得的细胞赋予健康益处的能力是 得到了实验和人体研究的支持。然而，对健康的有害影响有时也可能 发生.据报道，狗、袋獾和人类都患有传染性癌症， 主要是由母亲传给后代。据我们所知，以前的研究没有问过或解决过 自然获得的同种异体细胞有时可能是恶性肿瘤的来源。问 这可能导致了这个提议。接受器官移植的病人， 慢性免疫抑制器官移植受者（OTR）患有多种，经常出现， 鳞状细胞角化细胞癌（SCC）。与SCC相关的复发率和死亡率显著高于 与非免疫抑制个体相比增加。此R 03应用程序的目的是 研究OTR中SCC的同种异体DNA和细胞。目标1将开始通过询问DNA提取从 通过定量PCR（qPCR）检测Y染色体特异性序列的OTR SCC; 男性肿瘤中的男性DNA或女性肿瘤中存在男性DNA将被视为潜在的 同种异体癌的证据接下来将通过结合原位荧光进行细胞研究 Y和X染色体特异性探针杂交（FISH）和伴随免疫组织化学（IHC） 鉴定、定量和表型肿瘤标本中性别不匹配的细胞。Aim 2将调查OTR SCC以确定Aim 1中检测到的同种异体DNA和细胞的特定来源。在Aim 2系列的第1部分中 将招募成员，以便进行HLA和其他多态性基因分型。结果将 评估以鉴定家族成员特有的非共享HLA（或其他）多态性。提取的DNA 将从肿瘤样本中定量询问非共享多态性， 我们为此目的开发了一组HLA和其他多态性特异性qPCR测定。qPCR 测试将包括检测肿瘤中供体来源DNA的分析。对于家庭成员 目标2第2部分将对配对的肿瘤和外周血样本进行SNP阵列和分析 以确定肿瘤DNA是自体的还是同种异体的。