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

• 批准号: 10357439
• 负责人: Christiane Querfeld
• 金额: $ 26.69万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357439
• 关键词: Achievement; Algorithms; Area; Chromosomal translocation; Cities; Clinical; Cutaneous; Cutaneous Lymphoma; DNA; Data; Diagnosis; Disease; Future; Gene Fusion; Genes; Genetic; Genetic Transcription; 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; Ships; Site; Skin; Specimen; Spliced Genes; Survival Rate; TNFRSF8 gene; Tissues; Transcript; Work; accurate diagnosis; aggressive therapy; base; biomedical referral center; chemotherapy; clinical application; exome sequencing; experience; genetic information; genetic variant; genome sequencing; novel; overtreatment; personalized medicine; prevent; protein expression; sample collection; side effect; standard of care; therapeutic target; transcriptome sequencing; treatment planning; tumor; whole genome

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.

项目总结/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，需要强烈的化疗。 化疗原发性皮肤淋巴瘤样CD 30+淋巴组织增生性疾病（CD 30 +LPD） 丘疹病（LyP）和原发性皮肤间变性大细胞淋巴瘤（pcALCL）是无痛性的， 认可的实体。在组织学上很难区分sALCL、LyP和pcALCL;这通常会导致 CD 30 + LPD患者的误诊和过度治疗。LyP的5年生存率为92% 而对于pcALCL，当采用标准治疗、非靶向、皮肤定向治疗进行管理时，为90%。5年 ALK阴性sALCL的生存率为15-45%，需要积极治疗， 方面的影响.因此，临床上迫切需要区分LyP和pcALCL CD 30 + LPD与ALK- 阴性sALCL，因为每种都有不同的疾病，需要不同的治疗计划。 在个性化医疗的时代，医生和科学家们正在寻找肿瘤的分子特征 目的是开发用于诊断的标记物并指导潜在突变的治疗。分子 CD 30 + 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。 通过整合RNA的WGS和WES对基因组变异性和途径变化的上游分析， 为了鉴定表达的突变，我们预计完成拟议的研究将产生分子生物学上的结果。 LyP、pcALCL和sALCL的特征。这将改变目前单纯依赖临床的模式 病理相关性的一些专家在大型学术中心，这推迟了实现正确的 诊断超出了治疗选择的范围。然而，一个重要的障碍是获得统计上的 由于CD 30 + LPD是罕见的实体，因此需要大量标本才能完成有意义的分析。到 为了克服这一障碍，City of Hope已经建立了一个由五个三级转诊中心组成的联盟， 不仅贡献组织，还贡献临床信息。该联盟的独特之处在于它利用了多个 在淋巴瘤研究的临床、病理和转化领域有经验的研究人员分析了 迄今为止最大的标本群通过促进LyP和pcALCL的更准确诊断， 研究可能有助于防止过度治疗CD 30 + LPD患者的化疗， 消除化疗的不必要的副作用，包括由于治疗而缩短的总生存期。