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How Helpful is sequencing for Assessing Cancer Risk?

A study in Science Translational Medicine (published online 2012 Apr 2) by Johns Hopkins investigators indicates that whole-genome sequenc-ing will not provide solid predictive information for most people about their risk for many common diseases, including cancers. Furthermore, nega-tive genome test results may make people complacent about taking steps to detect or prevent disease.

“We’re definitely not saying that whole-genome sequencing is useless,” says Bert Vogelstein, MD, co-director of the Ludwig Center for Cancer Genetics at Johns Hopkins in Baltimore and a senior author of the study. “We’re just trying to show how useful it will be.”

To investigate the predictive poten-tial of whole-genome sequencing, Vogelstein’s team combed through data on thousands of monozygotic twin pairs entered in the Swedish Twin Registry, Danish Twin Registry, Finnish Twin Cohort, Norwegian National Birth Registry, and the National Academy of Sciences–National Research Council World War II Veteran Twin Registry.

“If the genome were the determin-ing factor for common diseases, then the prevalence of a specific disease in an individual whose twin has that disease can be used to determine how well whole-genome sequencing could predict an indi-vidual’s disease risk,” explains Vogelstein.

The researchers collected informa-tion on the incidence of 24 common diseases, including 9 types of cancer. Using sophisticated mathematical mod-els that they developed, the researchers calculated the ability of whole-genome sequencing to predict the risk of each disease based on typical thresholds that doctors use in decisions to start preven-tive or therapeutic measures.

Their analysis shows that whole-genome sequencing could alert most people to an increased risk of at least 1 disease, signaled by a positive test result, but most people would get negative test results for the majority of diseases studied, failing to forewarn them of the disease they may ultimately develop.

In the case of ovarian cancer, about 2% of women would test positive, de-fined here to mean that they have a 10%

increased risk of developing the disease. That means 98% of women would receive a negative test result, meaning they are not at excess risk—their risk of developing ovarian cancer is the same as in the general population.

“It would be nice if the test would say they are risk-free, but that’s not the case,” says Vogelstein. “It’s not go-ing to give them a ‘get-out-of-jail-free card.’ Cancers are largely the result of non-hereditary contributions.” For ex-ample, obese women are more likely to develop ovarian cancers.

Vogelstein notes that whole-genome sequencing will be extremely valuable in some cases, such as in families with a strong history of cancer. “But for most people, it won’t show risk much different from the general popula-tion,” he says. ≠

Photoacoustics Offers Penetrating images

Engineers from Washington University in St. Louis have developed an imaging technology called photoacous-tic tomography that allows scientists to produce high-resolution images of anatomic structures and chemical activi-ties concealed under centimeters of flesh (Science 2012;335:1458–62).

One goal for the technology is “to detect very-early-stage cancer, such as during colonoscopy or skin or breast cancer screens,” says principal investi-gator and bioengineer Lihong Wang, PhD. “By combining anatomic struc-ture with functional and metabolic

scott M. Lippman, MD, former chair of the Department of Thoracic/Head and Neck Medical Oncology and pro-fessor of cancer medicine and

cancer prevention at The University of Texas MD Anderson Cancer Center, started as director of Moores Cancer Center at the University of California, San Diego, on May 1. He succeeds Dennis A. Carson, MD, who served as director from 2003 to 2011, and Thomas Kipps, MD, PhD, who served as interim director since 2011.

Lippman’s major fields of research are translational and molecular studies of cancer risk, molecularly targeted drug development, and personalized therapy. He has been a leader in clinical and translational research planning and de-velopment through the National Cancer Institute’s (NCI) Clinical Trials Cooperative Group Program and currently sits on the NIH Clinical Trials/Translational Research Advisory Committee.

At Moores, an NCI-designated com-prehensive cancer center, Lippman plans to expand the portfolio of clini-cal and translational research, ramp up research-driven cancer therapy, and build on prevention programs.

stephen D. Nimer, MD, started his new position as the director of the Sylvester Comprehensive Cancer Center at the University of

Miami Miller School of Medicine in Florida on May 1. An internationally recognized expert on leukemia and stem cell transplantation, Nimer was previously the vice chair for faculty development at Memorial Sloan-Kettering Cancer Center’s (MSKCC) Department of Medicine.

At Sylvester, Nimer plans to develop and expand programs for breast, lung, prostate, and blood cancers, and recruit experts in bone marrow transplantation, mouse models of human cancer, and mo-lecular diagnostics.

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A technique that combines laser light with ultrasound can provide high-resolution images of anatomic structures and chemical activities, such as oxygen metabolism, deep in tissue. Here, photoacoustic tomography reveals a renal tumor xenograft at a depth of 2 mm (red) in a mouse ear (yellow).

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•  The U.s. supreme Court set aside a ruling by the Federal Circuit Court of Appeals about the Myriad Genetics patents of BRCA1 and BRCA2 genes, and sent the case back to the lower court for further review.

•  seven types of human tumors transplanted into mice shrank or dis-appeared when scientists treated the animals with a single antibody that masks the CD47 protein, which pro-tects cancer cells from macrophages and other immune cells. The anti-CD47 antibody treatment also blocked me-tastasis by highly aggressive tumors (PNAS published online 2012 Mar 26).

•  Roche’s antibody–drug conjugate trastuzumab emtansine (T-DM1) showed positive phase iii results for progression-free survival among women with HeR2-positive metastatic breast cancer who had previously re-ceived treatment with trastuzumab (Herceptin; Genentech) and a taxane.

•  south Korea’s National Center for Cancer Genomics is launching a collab-orative project to analyze breast cancer in Asian women.

•  The NIH’s new National Center for Advancing Translational Sciences (NCATS) and Lilly Research Laboratories (Indianapolis, IN) have agreed that the NCATs Pharmaceutical Collection of 3,800 approved and investigational medicines will be screened with Lilly’s Phenotypic Drug Discovery panel, designed to reveal novel mechanisms or pathways of potential medicines for cancer and other diseases. Results will be public at the NIH website at http:// tripod.nih.gov/npc.

•  “Data suggest that research participants and the public want and expect return of individual research results and inciden-tal findings, yet research practice has been not to return them,” said Susan Wolf, JD, of the University of Minnesota in Minneapolis during a discussion at the American Association for Cancer Research (AACR) Annual Meeting in Chicago in April. “We as a scientific com-munity are going to have to deal with this.”

•  In today’s cancer research, “most biomarker hypotheses are wrong,” Mark Ratain, MD, of the University of Chicago School of Medicine told a session at the AACR Annual Meeting 2012. “The field is filled with false discovery. ”

NotedNational Cancer Institute (NCI) in March. The designation makes UC Davis one of only 41 such centers in the United States.

To gain this status, the center was required to meet stringent criteria in research, education, and disseminating advances to patients. “It’s taken a lot of hard work to gain this new designa-tion,” says Ralph deVere White, MD, director of the newly named UC Davis Comprehensive Cancer Center.

Research partnerships played an instrumental role in achieving the “comprehensive” status. “Our work with the Lawrence Livermore National Laboratory, for example, has brought us technologies that are entirely unique and working with their scientists has been extremely fruitful,” says deVere White. “They have unique scientific ex-pertise and we have patients.”

He points to one project aimed at miniaturizing a proton beam accelera-tor to fit into a standard X-ray room. “The scientists were giving a talk about creating portable proton beam acceler-ators to test nuclear warheads,” deVere White recalls. “We realized that the same technology could help more can-cer patients if it were small enough.”

Another collaborative effort in-volves accelerator mass spectrometry (AMS), a highly sensitive method for analyzing molecular changes, to study the effectiveness of potential drugs in humans by giving doses that are about 1/100th of the normal amounts in therapy. Using AMS, researchers measure tumor cell response to “mi-crodoses” of drugs, such as cisplatin, and extrapolate the results to predict tumor response to therapeutic doses without the associated toxicity.

“We are not the biggest cancer cen-ter in the world,” deVere White adds. “But we have ways of leveraging our strength by forging partnerships.” ≠

information, we hope to make a much more accurate diagnosis.”

Designed to detect and image dif-ferent molecules, such as hemoglobin in red blood cells or melanin in skin, photoacoustic tomography blends light with ultrasound. First, researchers shine a pulse of laser light tuned to a given wavelength into the tissue. Molecules that absorb light of that color create a thermally induced pressure jump that creates a sound wave, which is captured using ultrasound detectors. To see an-other type of molecule, the investigators tune the laser to a different color.

Taken together, the data paint exquisite high-contrast images that clearly reveal and differentiate arteries, veins, and—with the help of injected dyes—tumor and other tissues. The data also reveal biochemical activities. For instance, because oxygenated and deoxygenated hemoglobin produce different colors, snapshots taken with 2 different laser colors can be compared and used to calculate the metabolic rate of oxy-gen for a given region of the body.

In previous work, Wang and colleagues used this technique to detect a doubling of oxygen metabolism just 1 week after implanting tumors in animal models.

Currently, the technology penetrates up to 7 cm through tissue. Because it operates well within accepted safety limits for laser and ultrasound devices, Wang sees the potential for the technology to reach deeper. Clinical trials are under way in collaboration with radiologists at Washington University School of Medicine to evaluate the use of photo-acoustic tomography to gauge the ef-ficacy of chemotherapy for breast cancer. Standard procedures monitor tumor structure, which changes slowly. By also monitoring functional and metabolic ac-tivity, it may be possible to predict efficacy in a span of weeks rather than months.

In addition, trials are planned to noninvasively assess the depth and volume of melanoma tumors and to reveal blood vessel density, oxygen saturation, and metabolic rates. ≠

UC Davis Cancer Center Gets “Comprehensive”

The University of California, Davis (UC Davis) Cancer Center was designated a Comprehensive Cancer Center by the

Medical physicist Ramsey Badawi, PhD, examines positron emission tomography scanning technology in development at UC Davis Comprehensive Cancer Center.

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For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

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2012;2:380-381. Published OnlineFirst March 29, 2012.Cancer Discovery     Photoacoustics Offers Penetrating Images

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