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.

项目摘要/摘要 ALK阴性全身性那内大细胞淋巴瘤（Salcl）是一种侵略性疾病，需要强烈 化学疗法。淋巴样的主要皮肤CD30+淋巴增生性疾病（CD30+ LPD） 乳头状（LYP）和原发性皮肤型大细胞淋巴瘤（PCALCL）是懒惰的，不太好 公认的实体。在组织学上区分Salcl，LYP和PCALCL是困难的。这通常会导致 CD30+ LPD患者的误诊和过度治疗。 LYP的5年生存率为92％ PCALCL使用标准的护理，非定位的皮肤定向疗法时，PCALCL为90％。 5年 Alk阴性的Salcl的存活率为15-45％，需要积极的治疗，并可能致命的侧面 效果。因此，临床需要将LYP和PCALCL CD30+ LPD与ALK-区分开 负salcl由于每个人都有不同的预后，需要不同的治疗计划。 在个性化医学时代，医生和科学家正在寻求以分子为特征 目的是开发用于诊断和指导疗法在基础突变的标记。分子 CD30+ LPD的表征不完整。整个基因组测序（WGS）的临床应用， 整个外显子组测序（WES）和RNA测序（RNA-Seq）将有助于区分这些实体。 通过上游分析基因组变异性和与RNA-集成的WES的途径变化 SEQ确定表达的突变，我们预计所提出的研究的完成将产生分子 LYP，PCALCL和SALCL的签名。这将改变当前仅依赖临床的范式 大型学术中心的一些专家的病理相关性，这延迟了正确的成就 诊断超出治疗选择点。但是，重大障碍是从统计上获得 由于CD30+ LPD是罕见的实体，因此大量的标本可以完成有意义的分析。到 克服了这一障碍，希望之城已经建立了一个由五个三级推荐中心组成的财团 不仅贡献组织，而且贡献临床信息。该财团是独一无二的 淋巴瘤研究的临床，病理和转化领域的经验丰富的研究者分析了 迄今为止最大的标本。通过促进对LYP和PCALCL的更准确诊断，该提议 研究将有可能有助于防止对CD30+ LPD患者进行化学疗法的过度治疗，从而 消除了化学疗法的不必要的副作用，包括由于治疗而缩短了总体存活率。