Genomic Analysis of Cutaneous CD30+ Lymphoproliferative Disorders

项目摘要/摘要 ALK阴性的系统性间变性大细胞淋巴瘤(SALCL)是一种侵袭性疾病，需要 化疗。淋巴瘤样原发皮肤CD30+淋巴组织增生性疾病 丘疹(LYP)和原发皮肤间变性大细胞淋巴瘤(PCALCL)是惰性的，不太好 已识别的实体。在组织学上很难区分sALCL、LYP和pcALCL；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% 如果采用标准的护理、非靶向、皮肤定向治疗，PCALCL的治愈率为90%。五年制 ALK阴性的sALCL的存活率为15%-45%，需要积极治疗可能致命的副作用- 效果。因此，临床上有必要区分LYP和pcALCL CD30+LPD与ALK- SALCL阴性，因为每种都有不同的预后，需要不同的治疗计划。 在个人化医学的时代，医生和科学家正寻求从分子上表征肿瘤。 目标是开发用于诊断和指导针对潜在突变的治疗的标记(S)。分子 CD30+LPD的特征是不完整的。全基因组测序技术的临床应用， 完整外显子组测序(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对基因组变异和途径变化的上游分析 为了鉴定表达的突变，我们预计拟议研究的完成将产生分子 LYP、pcALCL和sALCL的签名。这将改变目前单纯依靠临床的范式 大型学术中心几位专家的病理关联，这推迟了正确的实现 诊断超出了治疗选择的范围。然而，一个显著的障碍是在统计上获得 大量标本完成有意义的分析，因为CD30+LPD是罕见的实体。至 克服这一障碍，希望之城已经建立了一个由五个第三转诊中心组成的财团，以 不仅贡献组织，还贡献临床信息。该财团的独特之处在于它利用了多个 在淋巴瘤研究的临床、病理和翻译领域有经验的研究人员分析 迄今为止最大的一组标本。为了促进对LYP和PCALCL的更准确诊断，建议的 研究可能有助于防止CD30+LPD患者在化疗中过度治疗，因此 消除化疗的不必要副作用，包括因治疗而缩短总生存期。

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.