Identification of Lethal Melanomas at the Time of Diagnosis
诊断时鉴定致命性黑色素瘤
基本信息
- 批准号:10589941
- 负责人:
- 金额:$ 88.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdjuvant TherapyAffectAgeAmerican Joint Committee on CancerBRAF geneBenefits and RisksBiopsyCD3 AntigensCD8B1 geneCDKN2A geneCause of DeathCell DensityCellsCessation of lifeCharacteristicsClinical ResearchCutaneous MelanomaCyclin-Dependent Kinase Inhibitor 2ADNADangerousnessDataData CollectionDevelopmentDiagnosisDiagnostic Neoplasm StagingDiseaseEarly treatmentEligibility DeterminationEnvironmentEpidemiologyFundingGenderGenesGeneticGerm-Line MutationGoalsImmuneImmune responseImmune systemImmunologicsImmunotherapyIncidenceIndividualIntegration Host FactorsInternationalKnowledgeLiteratureLocalized DiseaseLymphocyte SubsetMalignant NeoplasmsMeasuresMediatingMetastatic MelanomaMolecular ProfilingMutationNF1 geneNeoplasm MetastasisNew AgentsNewly DiagnosedOncogenicPTEN genePathologicPathologyPatientsPhenotypePopulationPreventionProbabilityPublic HealthRecurrenceRegional DiseaseResearchResourcesRiskSamplingSignal TransductionSingle Nucleotide PolymorphismSkin CancerSomatic MutationStagingSun ExposureSystemic TherapyTP53 geneTestingTimeToxic effectTumor BurdenTumor Suppressor GenesTumor Suppressor ProteinsTumor stageTumor-Infiltrating LymphocytesUnited States Preventative Services Task ForceVariantVital Statuscohortcostcost effectivedisease natural historyeffective therapyepidemiologic datafollow-uphigh riskimprovedmelanomamortalityneoplastic cellovertreatmentpopulation basedprogrammed cell death ligand 1protein expressionresponsescreeningsurvival predictiontargeted treatmenttumortumor progression
项目摘要
PROJECT SUMMARY/ABSTRACT
Melanoma incidence rates continue to increase, whereas rates for most other cancers have
declined. Emerging systemic therapies for patients who have progressed to metastatic melanoma
are extending survival, but can be toxic, immensely costly and have variable efficacy. There are
efforts to extend the use of new agents to earlier disease stages as adjuvant therapies. Better
prediction of lethal melanoma at time of diagnosis is important to determine those who would
benefit from adjuvant therapies and, conversely, avoid toxicity in those whose melanomas are
unlikely to recur. Our central hypothesis is that it is possible to determine the combinations of
genetic alterations and immune responses in tumor samples that define a melanoma likely to be
ultimately lethal if not treated early. Conversely, we hypothesize that it will be possible to identify
somatic profiles of the tumors that indicate a very low risk of recurrence and ultimate death of the
patient, obviating the need for expensive, toxic treatments in such patients. We also hypothesize
that host characteristics, including germline variants in multiple genes, will be associated with
lethal melanoma. In Aim 1, we will test whether common somatic mutations in 104 genes/gene
regions in tumors are associated with death from melanoma. These genes include known
oncogenic drivers (BRAF, NRAS and TERT) and tumor suppressors (NF1, CDKN2A/CDKN2B,
PTEN and TP53). We will also test the hypothesis that measuring the immune cell milieu will add
information to survival prediction beyond conventional grading of tumor-infiltrating lymphocytes.
We will then explore how best to combine the genetic alterations, immune measures and 2018
American Joint Committee on Cancer (AJCC) tumor stage to identify those melanomas highly
likely to be ultimately lethal. In Aim 2, we will determine the extent to which the host characteristics
of germline variants, phenotypic characteristics, sun exposure, age and gender differ among
melanoma cases characterized as potentially lethal vs. nonlethal, leading to the identification of
a subset of the population at high risk for lethal melanoma. This research will be undertaken using
a resource that is uniquely suited to addressing these issues, the international, population-based
Genes, Environment and Melanoma (GEM) Study, which collected epidemiologic data, pathology
and tumor sections for a large cohort of incident primary cutaneous melanoma cases diagnosed
in the year 2000. We have available a minimum of 10 years of follow-up of vital status and cause
of death for all cases. GEM is an ideal resource because the end of the follow-up period precedes
the targeted and immune therapy era, allowing us to study factors affecting the natural history of
the disease. The vast majority of GEM cases (more than 85%) presented with local disease, and
we project that at least 80% of the deaths will occur in cases initially presenting with local or
regional disease. The results should enhance our ability to identify lethal melanomas at an early
stage when treatments may be more effective and, conversely, to identify melanomas with a very
low risk of recurrence for which unnecessary and potentially toxic treatments can be confidently
avoided.
项目概要/摘要
黑色素瘤的发病率持续上升,而大多数其他癌症的发病率却有所下降
拒绝了。针对已进展为转移性黑色素瘤患者的新兴全身疗法
可以延长生存期,但可能有毒、成本高昂且功效参差不齐。有
努力将新药的使用扩展到早期疾病阶段作为辅助治疗。更好的
诊断时预测致命性黑色素瘤对于确定哪些人会
对于患有黑色素瘤的患者来说,可以从辅助治疗中受益,并且可以避免毒性。
不太可能复发。我们的中心假设是可以确定以下组合
肿瘤样本中的基因改变和免疫反应可能定义为黑色素瘤
如果不及早治疗,最终会致命。相反,我们假设可以识别
肿瘤的体细胞特征表明复发和最终死亡的风险非常低
患者,避免了对此类患者进行昂贵的有毒治疗的需要。我们还假设
宿主特征,包括多个基因的种系变异,将与
致命的黑色素瘤。在目标1中,我们将测试104个基因/基因中是否存在常见的体细胞突变
肿瘤中的区域与黑色素瘤死亡相关。这些基因包括已知的
致癌驱动因子(BRAF、NRAS 和 TERT)和肿瘤抑制因子(NF1、CDKN2A/CDKN2B、
PTEN 和 TP53)。我们还将测试以下假设:测量免疫细胞环境会增加
超越肿瘤浸润淋巴细胞常规分级的生存预测信息。
然后我们将探索如何最好地将基因改变、免疫措施和 2018
美国癌症联合委员会 (AJCC) 肿瘤分期可高度识别黑色素瘤
最终可能是致命的。在目标 2 中,我们将确定宿主特征的程度
种系变异、表型特征、阳光照射、年龄和性别之间存在差异
黑色素瘤病例被定性为潜在致命与非致命,从而确定了
致命黑色素瘤高危人群的一个子集。这项研究将使用
一个特别适合解决这些问题的资源,即国际、以人口为基础的资源
基因、环境和黑色素瘤 (GEM) 研究,收集流行病学数据、病理学数据
以及诊断的大量原发性皮肤黑色素瘤病例的肿瘤切片
2000 年。我们对生命状况和原因进行了至少 10 年的跟踪
所有病例的死亡。创业板是理想的资源,因为后续期结束之前
靶向和免疫治疗时代,使我们能够研究影响自然史的因素
这种疾病。绝大多数 GEM 病例(超过 85%)表现为局部疾病,并且
我们预计,至少 80% 的死亡将发生在最初就诊于当地或当地的病例中。
区域性疾病。结果应该会增强我们及早识别致命黑色素瘤的能力
治疗可能更有效的阶段,相反,可以非常有效地识别黑色素瘤
复发风险低,可以自信地进行不必要的和潜在毒性的治疗
避免了。
项目成果
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HODA A ANTON-CULVER其他文献
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{{ truncateString('HODA A ANTON-CULVER', 18)}}的其他基金
Identification of Lethal Melanomas at the Time of Diagnosis
诊断时鉴定致命性黑色素瘤
- 批准号:
10379429 - 财政年份:2020
- 资助金额:
$ 88.87万 - 项目类别:
Identification of Lethal Melanomas at the Time of Diagnosis
诊断时鉴定致命性黑色素瘤
- 批准号:
9883462 - 财政年份:2020
- 资助金额:
$ 88.87万 - 项目类别:
California Precision Medicine Research Program Consortium
加州精准医学研究计划联盟
- 批准号:
9893367 - 财政年份:2018
- 资助金额:
$ 88.87万 - 项目类别:
California Precision Medicine Research Program Consortium
加州精准医学研究计划联盟
- 批准号:
10356359 - 财政年份:2018
- 资助金额:
$ 88.87万 - 项目类别:
California Precision Medicine Research Program Consortium
加州精准医学研究计划联盟
- 批准号:
10788837 - 财政年份:2018
- 资助金额:
$ 88.87万 - 项目类别:
California Precision Medicine Research Program Consortium
加州精准医学研究计划联盟
- 批准号:
10597722 - 财政年份:2018
- 资助金额:
$ 88.87万 - 项目类别:
GENETIC EPIDEMIOLOGY OF PANCREAS CANCER FAMILIES: A CANCER GENETICS NETWORK PILO
胰腺癌家族的遗传流行病学:癌症遗传学网络 PILO
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8166943 - 财政年份:2009
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$ 88.87万 - 项目类别:
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