Genomic Analysis of Cutaneous CD30+ Lymphoproliferative Disorders

皮肤 CD30 淋巴细胞增殖性疾病的基因组分析

基本信息

批准号：
10559641
负责人：
Christiane Querfeld
金额：
$ 21.59万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559641
关键词：
Achievement Algorithms Area Chromosomal translocation Cities Clinical Cutaneous Cutaneous Lymphoma DNA Data Diagnosis Disease Future Gene Fusion Genes Genetic Genomics Goals Histologic Histology Indolent Ki-1 Large-Cell Lymphoma Lead Lymphoma Lymphomatoid papulosis Lymphoproliferative Disorders Modification Molecular Molecular Profiling Mutation Mutation Spectra Nodal Pathologic Pathology Pathway interactions Patients Pattern Physicians Pilot Projects Prognosis RNA Rare Diseases Research Research Personnel Sampling Scientist Selection for Treatments Site Skin Specimen Spliced Genes Survival Rate TNFRSF8 gene Therapeutic Tissues Transcript Work accurate diagnosis aggressive therapy biomedical referral center chemotherapy clinical application data exchange exome sequencing experience genetic information genetic variant genome sequencing novel overtreatment personalized medicine posttranscriptional prevent protein expression sample collection side effect standard of care therapeutic target transcriptome sequencing treatment planning tumor whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT ALK-negative systemic anaplastic large cell lymphoma (sALCL) is an aggressive disease requiring intense chemotherapy. The primary cutaneous CD30+ lymphoproliferative disorders (CD30+LPD) of lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL) are indolent, less well recognized entities. Distinguishing sALCL, LyP, and pcALCL histologically is difficult; this often leads to misdiagnosis and overaggressive treatment of patients with CD30+ LPD. The 5-year survival rate is 92% for LyP and 90% for pcALCL when managed with standard of care, non-targeted, skin-directed therapies. The 5-year survival rate is 15-45% for ALK-negative sALCL and requires aggressive treatment with potentially fatal side- effects. Thus, there is a critical clinical need to differentiate the LyP and pcALCL CD30+ LPD from ALK- negative sALCL since each has distinct prognoses and requires different treatment plans. In the era of personalized medicine, physicians and scientists are looking to characterize tumors molecularly with the goal of developing markers for diagnosis and directing therapy at the underlying mutation(s). Molecular characterization is incomplete for CD30+ LPD. The clinical application of whole genome sequencing (WGS), whole exome sequencing (WES) and RNA sequencing (RNA-seq) will help differentiate among these entities. Through upstream analysis of genomic variability and pathway changes by WGS and WES integrated with RNA- seq to identify expressed mutations, we anticipate that completion of the proposed research will yield molecular signatures of LyP, pcALCL, and sALCL. This will change the current paradigm of relying solely on clinical pathologic correlation by a few experts at large academic centers, which delays achievement of the correct diagnosis beyond the point of treatment selection. However, a significant barrier is obtaining a statistically significant number of specimens to complete a meaningful analysis, since CD30+ LPD are rare entities. To overcome this obstacle, City of Hope has already established a consortium of five tertiary referral centers to contribute not only tissue but also clinical information. The consortium is unique in that it leverages multiple experienced investigators in the clinical, pathologic, and translational areas of lymphoma research who analyze the largest group of specimens to date. By facilitating more accurate diagnosis of LyP and pcALCL, the proposed studies will potentially help prevent over-treatment of patients with CD30+ LPD with chemotherapy, thus eliminating the unnecessary side-effects of chemotherapy, including shortened overall survival due to treatment.

项目概要/摘要 ALK 阴性系统性间变性大细胞淋巴瘤 (sALCL) 是一种侵袭性疾病，需要强烈的治疗化疗。类淋巴瘤的原发性皮肤 CD30+ 淋巴增殖性疾病 (CD30+LPD) 丘疹病 (LyP) 和原发性皮肤间变性大细胞淋巴瘤 (pcALCL) 呈惰性，病情较差认可的实体。从组织学上区分 sALCL、LyP 和 pcALCL 很困难；这常常导致 CD30+ LPD 患者的误诊和过度治疗。 LyP 的 5 年生存率为 92% 当采用标准护理、非靶向、皮肤导向疗法进行治疗时，pcALCL 的死亡率为 90%。 5年期 ALK 阴性 sALCL 的生存率为 15-45%，需要积极治疗，并可能致命影响。因此，临床上迫切需要区分 LyP 和 pcALCL CD30+ LPD 与 ALK- 阴性 sALCL，因为每种疾病都有不同的预后并需要不同的治疗计划。在个性化医疗时代，医生和科学家正在寻求从分子角度表征肿瘤目标是开发用于诊断的标记物并指导针对潜在突变的治疗。分子 CD30+ LPD 的表征不完整。全基因组测序（WGS）的临床应用，全外显子组测序 (WES) 和 RNA 测序 (RNA-seq) 将有助于区分这些实体。通过与 RNA 整合的 WGS 和 WES 对基因组变异和通路变化进行上游分析 seq 来识别表达的突变，我们预计完成拟议的研究将产生分子 LyP、pcALCL 和 sALCL 的签名。这将改变目前仅依赖临床的模式大型学术中心的少数专家的病理相关性，延迟了正确的实现诊断超出了治疗选择的范围。然而，一个重大障碍是获得统计数据由于 CD30+ LPD 是罕见的实体，因此需要大量样本才能完成有意义的分析。到为了克服这一障碍，希望之城已经建立了一个由五个三级转诊中心组成的联盟，以不仅提供组织信息，还提供临床信息。该联盟的独特之处在于它利用了多种在淋巴瘤研究的临床、病理和转化领域经验丰富的研究人员，他们分析迄今为止最大的标本群。通过促进 LyP 和 pcALCL 的更准确诊断，建议研究可能有助于防止 CD30+ LPD 患者接受化疗的过度治疗，因此消除化疗不必要的副作用，包括因治疗而缩短的总生存期。