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已有 1227 次阅读 2018-1-25 01:57 |个人分类:新观察|系统分类:海外观察| 血检, 癌症诊断, CancerSEEK |文章来源:转载


ImageElizabeth Cook_Kaitlin Lindsay.jpg

Credit: Elizabeth Cook and Kaitlin Lindsay

约翰•霍普金斯大学Kimmel 癌症研究中心(Johns Hopkins Kimmel Cancer Center)的研究人员开发了一种能够筛选八种常见类型癌症的单一血液检测,该方法还有助于癌症的定位。


该文资深作者,肿瘤与病理学教授Nickolas Papadopoulos, Ph.D.,表示:“将选定的不同生物标记物联合用于早期检测有可能改变我们筛查癌症的方式,该检测是基于与药物组合治疗癌症相同的原理。”


该文第一作者,约翰•霍普金斯大学医学院的M.D.-Ph.D.学生Joshua Cohen说:“循环肿瘤DNA突变可能是癌症的高度特异性标记物。为了利用这种内在的特异性,我们试图开发一个小而强大的特异性标记物组合来检测绝大多数癌症的至少一个突变。而事实上,使该组合规模尽量的小,这对于减少假阳性结果至关重要,并且还能让人负担得起筛查检测费用。”

研究人员探索了数百个基因和40个蛋白质标记物,并最终将其数量减少到16个基因和8个蛋白。 他们指出,这种分子检测旨在仅进行癌症筛查,因此它与其它分子检测方法有所不同,后者是旨在通过分析大量癌症相关基因来发现癌症治疗的靶点。

在这个研究中,该测试对癌症的特异性大于99%。肿瘤学教授兼路德维希中心(the Ludwig Center)的联合主任Kenneth Kinzler, Ph.D.表示:“非常高的特异性是必不可少的,因为假阳性结果会使患者接受不必要的有创随访检查和手术以确认癌症的存在。在被用于812名健康对照时,该检测仅产生了7个假阳性结果。

该检测在1,005名非转移性I至III期卵巢癌,肝癌,胃癌,胰腺癌,食管癌,结直肠癌,肺癌或乳腺癌患者中进行了评估。 该检测的总体敏感度中位数(即发现癌症的能力)为70%,其范围从卵巢癌的98%至乳腺癌的33%。对于目前不具备筛查检测的五种癌症(卵巢癌,肝癌,胃癌,胰腺癌和食管癌)而言,其敏感度在69%至98%之间。

开发了该检测的算法的肿瘤和生物统计副教授Cristian Tomasetti, Ph.D.表示:“我们的分类方法的一个新颖之处在于,它将观察DNA突变以及几种蛋白质表达水平的可能性结合起来,以得出最终的检测结果。该方法的另一个新颖之处在于它使用了机器学习来使检测能够在83%的患者中把肿瘤准确定位到很少的几个解剖部位。”

虽然目前的检测还不能检测出每一种癌症,但是它能够检测到很多以前很可能不会被发现的癌症。路德维希中心(the Ludwig Center)的联合主任,Clayton肿瘤学教授兼霍华德•休斯医学研究所(Howard Hughes Medical Institute)研究员Bert Vogelstein, M.D.,表示:“在大多数最具希望的癌症治疗方法中,很多是仅能使少数癌症患者获益。如果我们要在早期癌症检测方面取得进展,我们必须以更现实的方式进行研究,要认识到没有任何一种方法可以检测到所有的癌症。”

为了确定CancerSEEK检测应该包括的分析物,研究小组使用了30多年来约翰•霍普金斯大学路德维希中心(Johns Hopkins Ludwig Center)的癌症遗传学研究数据,以及来自许多其它机构的数据:路德维希中心是首个癌症遗传图谱的诞生地。


医学,外科和放射学副教授,消化内科临床主任和多学科胰腺囊肿项目主任Anne Marie Lennon, M.D., Ph.D.说:“最理想的状态是,癌症能够被尽早地检测出来,并且通过手术就可以治愈;即使是单纯手术无法治愈的癌症,在其疾病发展程度较低时,对治疗的反应也会更好。”

Single Blood Test Screens for Eight Cancer Types

Provides unique new framework for early detection of the most common cancers
Release Date: January 18, 2018

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Credit: Elizabeth Cook and Kaitlin Lindsay  

Johns Hopkins Kimmel Cancer Center researchers developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer.

The test, called CancerSEEK, is a unique noninvasive, multianalyte test that simultaneously evaluates levels of eight cancer proteins and the presence of cancer gene mutations from circulating DNA in the blood. The test is aimed at screening for eight common cancer types that account for more than 60 percent of cancer deaths in the U.S. Five of the cancers covered by the test currently have no screening test.

“The use of a combination of selected biomarkers for early detection has the potential to change the way we screen for cancer, and it is based on the same rationale for using combinations of drugs to treat cancers,” says Nickolas Papadopoulos, Ph.D., senior author and professor of oncology and pathology.

The findings were published online by Science on Jan. 18, 2018.

“Circulating tumor DNA mutations can be highly specific markers for cancer. To capitalize on this inherent specificity, we sought to develop a small yet robust panel that could detect at least one mutation in the vast majority of cancers,” says Joshua Cohen, an M.D.-Ph.D. student at the Johns Hopkins University School of Medicine and the paper’s first author. “In fact, keeping the mutation panel small is essential to minimize false-positive results and keep such screening tests affordable.”

The investigators initially explored several hundred genes and 40 protein markers, whittling the number down to segments of 16 genes and eight proteins. They point out that this molecular test is solely aimed at cancer screening and, therefore, is different from other molecular tests, which rely on analyzing large numbers of cancer-driving genes to identify therapeutically actionable targets.

In this study, the test had greater than 99 percent specificity for cancer. “Very high specificity was essential because false-positive results can subject patients to unnecessary invasive follow-up tests and procedures to confirm the presence of cancer,” says Kenneth Kinzler, Ph.D., professor of oncology and co-director of the Ludwig Center. The test was used on 812 healthy controls and produced only seven false-positive results.

The test was evaluated on 1,005 patients with nonmetastatic, stages I to III cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung or breast. The median overall sensitivity, or the ability to find cancer, was 70 percent and ranged from a high of 98 percent for ovarian cancer to a low of 33 percent for breast cancer. For the five cancers that have no screening tests—ovarian, liver, stomach, pancreatic and esophageal cancers—sensitivity ranged from 69 percent to 98 percent.

“A novelty of our classification method is that it combines the probability of observing various DNA mutations together with the levels of several proteins in order to make the final call,” says Cristian Tomasetti, Ph.D., associate professor of oncology and biostatistics, who developed the algorithm. “Another new aspect of our approach is that it uses machine learning to enable the test to accurately determine the location of a tumor down to a small number of anatomic sites in 83 percent of patients.”

Although the current test does not pick up every cancer, it identifies many cancers that would likely otherwise go undetected. “Many of the most promising cancer treatments we have today only benefit a small minority of cancer patients, and we consider them major breakthroughs. If we are going to make progress in early cancer detection, we have to begin looking at it in a more realistic way, recognizing that no test will detect all cancers,” says Bert Vogelstein, M.D., co-director of the Ludwig Center, Clayton Professor of Oncology and Howard Hughes Medical Institute investigator.

To zero in on the analytes they included in their CancerSEEK test, the research team pulled data from more than three decades of cancer genetics research generated at their Ludwig Center at Johns Hopkins, where the first genetic blueprints for cancer were created, as well as data from many other institutions.

To precisely determine the optimal number of DNA bases to assess in the CancerSEEK test, the researchers used a method based on diminishing returns. “The more DNA bases you assay, the more mutations you are capable of finding, but eventually you reach a point of diminishing returns,” explains Cohen. “We designed our test to reflect this point of diminishing returns, including the DNA markers that were useful to detecting the cancers and eliminating those that did not add benefit.” The result was a relatively small panel of highly selective DNA markers.

“This test represents the next step in changing the focus of cancer research from late-stage disease to early disease, which I believe will be critical to reducing cancer deaths in the long term,” says Vogelstein.

CancerSEEK is noninvasive and can, in principle, be administered by primary care providers at the time of other routine blood work. “This has the potential to substantially impact patients. Earlier detection provides many ways to improve outcomes for patients. Optimally, cancers would be detected early enough that they could be cured by surgery alone, but even cancers that are not curable by surgery alone will respond better to systemic therapies when there is less advanced disease,” says Anne Marie Lennon, M.D., Ph.D., associate professor of medicine, surgery and radiology, clinical director of gastroenterology and director of the Multidisciplinary Pancreatic Cyst Program.

The investigators feel that a test that will be used routinely for cancer screening must have a cost in line with or less than other currently available screening tests for single cancers, such as colonoscopy. They envision that the CancerSEEK test will eventually cost less than $500.

Larger studies of the test are currently under way.

In addition to Cohen, Papadopoulos, Lennon, Tomasetti, Kinzler and Vogelstein, other participants include Lu Li, Yuxuan Wang, Christopher Thorburn, Bahman Afsari, Ludmila Danilova, Christopher Douville, Ammar Javed, Fay Wong, Austin Mattox, Ralph Hruban, Christopher Wolfgang, Michael Goggins, Marco Dal Molin, Tian-Li Wang, Richard Roden, Alison Klein, Janine Ptak, Lisa Dobbyn, Joy Schaefer, Natalie Silliman, Maria Popoli, Joshua Vogelstein, James Browne, Robert Schoen, Randall Brand, Jeanne Tie, Peter Gibbs, Hui-Li Wong, Aaron Mansfield, Jin Jen, Samir Hanash, Massimo Falconi, Peter Allen, Shibin Zhou, Chetan Bettegowda and Luis Diaz.

The research was supported by the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, The Commonwealth Fund, the John Templeton Foundation, the Clinomics Program, Mayo Clinic Center for Individualized Medicine, the Mayo Clinic Biobank, the Sol Goldman Center for Pancreatic Cancer Research, The Michael Rolfe Pancreatic Cancer Research Foundation, the Benjamin Baker Scholarship, the Gray Foundation, the Early Detection Research Network, Susan Wojcicki and Dennis Troper, the Marcus Foundation, the Conrad N. Hilton Foundation, the Howard Hughes Medical Institute, and National Institutes of Health Grants P50-CA62924, P50-CA102701, CA06973, GM-07309, and U01CA152753.

COI: Nickolas Papadopoulos, Shibin Zhou, Kenneth Kinzler, Luis Diaz and Bert Vogelstein are founders of Personal Genome Diagnostics, Inc. and PapGene, Inc. Vogelstein and Kinzler are on the Scientific Advisory Board of Sysmex-Inostics, and Vogelstein is on the Scientific Advisory Board of Exelixis GP. These companies and others have licensed technologies from Johns Hopkins, and Papadopoulos, Kinzler, Diaz and Vogelstein receive equity or royalties from these licenses. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

More information, including a copy of the paper, can be found online at the Science press package at http://www.eurekalert.org/jrnls/sci. You will need your user ID and password to access this information.




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