Understanding Long Tail Driver Mutations in Cancer

了解癌症中的长尾驱动基因突变

• 批准号: 10090571
• 负责人: Nikolaus Schultz
• 金额: $ 41.08万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090571
• 关键词: Adoption; Algorithms; Alleles; Biological; Biological Response Modifier Therapy; Cancer Patient; Cells; Clinical; Clinical Research; Clinical Trials; Computing Methodologies; Coupled; Data; Disease; Eligibility Determination; Enrollment; Foundations; Frequencies; Genes; Genetic; Genome; Genomic approach; Genotype; Goals; Impairment; In complete remission; Individual; Institution; Institutional Review Boards; Knowledge; Laboratories; Lead; Lesion; Link; MEKs; Malignant Neoplasms; Measures; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Methods; Molecular; Molecular Abnormality; Mutation; Oncogenes; Oncology; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Population; Precision therapeutics; Proto-Oncogene Proteins c-akt; Recurrence; Somatic Mutation; Structure; Surveys; Tail; Therapeutic; Therapeutic Trials; Time; Validation; biomarker selection; cancer care; cancer genome; cancer therapy; clinical care; clinical phenotype; clinical sequencing; clinical translation; clinically actionable; co-clinical trial; cohort; computer framework; design; dosage; driver mutation; drug sensitivity; effective therapy; exome sequencing; flexibility; improved; in vitro Model; inhibitor/antagonist; innovation; interdisciplinary approach; molecular phenotype; mutant; novel; novel therapeutic intervention; participant enrollment; patient population; phenotypic data; prospective; response; targeted treatment; therapeutic target; translational genomics; treatment optimization; treatment response; tumor

PROJECT SUMMARY/ABSTRACT The transition to genomically driven oncology has begun, catalyzed in part by efforts to rationally design effective therapies targeting the specific molecular aberrations on which individual tumors depend. This has led, inexorably, to the prospective clinical sequencing of patients with active disease to guide their cancer care. Nevertheless, a fundamental gap remains. The shift toward larger panel and whole exome sequencing has led to the identification of increasing numbers of somatic mutations in even presumed actionable cancer genes, the vast majority of which are in the so-called long right tail and lack biological or clinical validation. This significantly impairs our ability to use findings generated by prospective profiling to guide patient care. We have recently shown that such long-tail driver mutations can be the genetic basis of extraordinary responses to systemic cancer therapy. We went on to show that a systematic survey utilizing population-scale cancer genome data coupled to computational methodologies reveals similar long-tail drivers of both biological and therapeutic significance. These findings underscore the importance of long-tail driver mutations in cancer, but without a systematic approach for rapidly prioritizing and functionally and clinically validating these somatic mutations, the gap in our understanding of the clinically actionable genome will widen. We propose to overcome this urgent clinical challenge by establishing a robust and sophisticated framework for elucidating novel driver mutations in the long tail. We will first establish a comprehensive computational framework that identifies and prioritizes long-tail driver mutations that leverages not only population-scale data but integrates orthogonal measures of selection. We will then apply these methods to a cohort of greater than 50,000 prospectively sequenced active cancer patients at our Center, all possessing detailed clinical, outcome, and treatment response data, results from which can lead to the enrollment of patients on genotype-directed clinical trials. Finally, we will perform functional studies of novel long-tail driver mutations revealed by these analyses in genes for which there is an open basket study at our institution, thereby establishing a co-clinical framework by which laboratory functional validation can be paired with patient treatment response. Together, these studies seek to establish a computational-experimental framework for identifying functional mutations in the long tail that expand the treatment options for molecularly defined populations of cancer patients.

项目总结/摘要 向基因组驱动的肿瘤学的转变已经开始，部分原因是合理设计的努力 针对个体肿瘤所依赖的特定分子畸变的有效疗法。这 无情地导致了对活动性疾病患者的前瞻性临床测序，以指导他们的癌症护理。 然而，一个根本性的差距仍然存在。向更大的面板和整个外显子组测序的转变导致了 到甚至在假定的可作用的癌症基因中鉴定越来越多的体细胞突变， 其中绝大多数是在所谓的长右尾，缺乏生物学或临床验证。这 显著削弱了我们使用前瞻性分析所产生的发现来指导患者护理的能力。我们有 最近表明，这种长尾驱动突变可能是对 全身癌症治疗。我们继续表明，一项利用人口规模癌症的系统调查 结合计算方法的基因组数据揭示了生物学和生物学的类似长尾驱动因素， 治疗意义这些发现强调了长尾驱动突变在癌症中的重要性， 如果没有一种系统的方法来快速优先化和功能性和临床验证这些体细胞 突变，我们对临床可操作基因组的理解的差距将扩大。我们建议 通过建立一个强大而复杂的框架来阐明 长尾中的新驱动突变。我们将首先建立一个全面的计算框架， 识别并优先考虑长尾驱动突变，不仅利用人口规模的数据， 选择的正交措施。然后，我们将这些方法应用于超过50，000人的队列 前瞻性测序的活动性癌症患者在我们的中心，所有拥有详细的临床，结果， 治疗反应数据，其结果可导致患者入组基因型导向的临床试验 审判最后，我们将对这些分析揭示的新型长尾驱动突变进行功能研究 在我们机构进行的开放篮子研究中， 实验室功能验证可与患者治疗反应配对。所有这些 研究试图建立一个计算-实验框架，用于识别基因组中的功能突变。 长尾，扩大了分子定义的癌症患者群体的治疗选择。

项目成果

Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer.

• DOI: 10.1158/1078-0432.ccr-18-0412
• 发表时间: 2018-12-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Soumerai TE;Donoghue MTA;Bandlamudi C;Srinivasan P;Chang MT;Zamarin D;Cadoo KA;Grisham RN;O'Cearbhaill RE;Tew WP;Konner JA;Hensley ML;Makker V;Sabbatini P;Spriggs DR;Troso-Sandoval TA;Charen AS;Friedman C;Gorsky M;Schweber SJ;Middha S;Murali R;Chiang S;Park KJ;Soslow RA;Ladanyi M;Li BT;Mueller J;Weigelt B;Zehir A;Berger MF;Abu-Rustum NR;Aghajanian C;DeLair DF;Solit DB;Taylor BS;Hyman DM
• 通讯作者: Hyman DM

Accelerating Discovery of Functional Mutant Alleles in Cancer.

• DOI: 10.1158/2159-8290.cd-17-0321
• 发表时间: 2018-03
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Chang MT;Bhattarai TS;Schram AM;Bielski CM;Donoghue MTA;Jonsson P;Chakravarty D;Phillips S;Kandoth C;Penson A;Gorelick A;Shamu T;Patel S;Harris C;Gao J;Sumer SO;Kundra R;Razavi P;Li BT;Reales DN;Socci ND;Jayakumaran G;Zehir A;Benayed R;Arcila ME;Chandarlapaty S;Ladanyi M;Schultz N;Baselga J;Berger MF;Rosen N;Solit DB;Hyman DM;Taylor BS
• 通讯作者: Taylor BS

Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis.

• DOI: 10.1158/1078-0432.ccr-17-2655
• 发表时间: 2018-04-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chang MT;Penson A;Desai NB;Socci ND;Shen R;Seshan VE;Kundra R;Abeshouse A;Viale A;Cha EK;Hao X;Reuter VE;Rudin CM;Bochner BH;Rosenberg JE;Bajorin DF;Schultz N;Berger MF;Iyer G;Solit DB;Al-Ahmadie HA;Taylor BS
• 通讯作者: Taylor BS

AKT Inhibition in Solid Tumors With AKT1 Mutations.

• DOI: 10.1200/jco.2017.73.0143
• 发表时间: 2017-07-10
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Hyman DM;Smyth LM;Donoghue MTA;Westin SN;Bedard PL;Dean EJ;Bando H;El-Khoueiry AB;Pérez-Fidalgo JA;Mita A;Schellens JHM;Chang MT;Reichel JB;Bouvier N;Selcuklu SD;Soumerai TE;Torrisi J;Erinjeri JP;Ambrose H;Barrett JC;Dougherty B;Foxley A;Lindemann JPO;McEwen R;Pass M;Schiavon G;Berger MF;Chandarlapaty S;Solit DB;Banerji U;Baselga J;Taylor BS
• 通讯作者: Taylor BS

Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA.

• DOI: 10.1038/s42255-021-00378-8
• 发表时间: 2021-04
• 期刊: NATURE METABOLISM
• 影响因子: 20.8
• 作者: Gorelick, Alexander N.;Kim, Minsoo;Chatila, Walid K.;La, Konnor;Hakimi, A. Ari;Berger, Michael F.;Taylor, Barry S.;Gammage, Payam A.;Reznik, Ed
• 通讯作者: Reznik, Ed