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Archive for the ‘Cancer Genomics’ Category

New blood test accurately detects presence of breast cancer and monitors response to treatment

Posted in Cancer Screening, Diagnostics and Lab Tests, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood on May 15, 2014| Leave a Comment »

New blood test accurately detects presence of breast cancer and monitors response to treatment

Reporter: Aviva Lev-Ari, PhD, RN

 

See on Scoop.it – Cardiovascular Disease: PHARMACO-THERAPY

Johns Hopkins Kimmel Cancer Center investigators report they have designed a blood test that accurately detects the presence of advanced breast cancer and also holds promise for precisely monitoring response to cancer treatment.

 

The test, called the cMethDNA assay, accurately detected the presence of cancer DNA in the blood of patients with metastatic breast cancers up to 95 percent of the time in laboratory studies. The findings were described in the April 15 issue of the journal Cancer Research.

Currently, there is no useful laboratory test to monitor patients with early stage breast cancer who are doing well, but could have an asymptomatic recurrence, says Saraswati Sukumar, Ph.D., who is the Barbara B. Rubenstein Professor of Oncology and co-director of the Breast Cancer Program at the Johns Hopkins Kimmel Cancer Center.

 

Generally, radiologic scans and standard blood tests are indicated only if a woman complains of symptoms, such as bone aches, shortness of breath, pain, or worrisome clinical exam findings. Otherwise, routine blood tests or scans in asymptomatic patients often produce false positives, leading to additional unnecessary tests and biopsies, and have not been shown to improve survival outcomes in patients with early stage breast cancer who develop a recurrence.

 

Sukumar, also a professor of pathology at Johns Hopkins, says that the current approach to monitoring for recurrence is not ideal, and that “the goal is to develop a test that could be administered routinely to alert the physician and patient as soon as possible of a return of the original cancer in a distant spot. With the development of cMethDNA, we’ve taken a first big step toward achieving this goal.”

 

To design the test, Sukumar and her team scanned the genomes of primary breast cancer patients, as well as DNA from the blood of metastatic cancer patients. They selected 10 genes specifically altered in breast cancers, including newly identified genetic markers AKR1B1, COL6A2, GPX7, HIST1H3C, HOX B4, RASGRF2, as well as TM6SF1, RASSF1, ARHGEF7, and TMEFF2, which Sukumar’s team had previously linked to primary breast cancer.

 

The test, developed by Sukumar, collaborator Mary Jo Fackler, Ph.D., and other scientists, detects so-called hypermethyation, a type of chemical tag in one or more of the breast cancer-specific genes present in tumor DNA and detectable in cancer patients’ blood samples. Hypermethylation often silences genes that keep runaway cell growth in check, and its appearance in the DNA of breast cancer-related genes shed into the blood indicates that cancer has returned or spread.

See on www.news-medical.net

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Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection

Posted in Calcium, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Prevention: Research & Programs, Cancer Screening, Gene Regulation, Personalized and Precision Medicine & Genomic Research, Population Health Management, Nutrition and Phytochemistry, Variation in human protein-coding regions, tagged , , , , , , on April 12, 2013| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Ca Prevention: Calcium May Protect Colon

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

WASHINGTON — Increasing calcium intake may lower the risk of colorectal adenomas in people who are at increased risk of the precancerous lesions due to variations in two genes, researchers reported here.

In a two-phase, case-control study of nearly 6,000 subjects, high calcium intake was associated with a significantly reduced risk of adenoma among those who carried variants in the KCNJ and SLC12A1 genes.

High calcium intake was not associated with a reduced risk of colorectal adenoma among those with no variants in KCNJ and SLC12A1, both of which are essential to calcium reabsorption in the kidney, reported Xiangzhu Zhu, MD, of Vanderbilt-Ingram Cancer Center at the American Association for Cancer Research meeting here.

The two-phase study was undertaken to explore whether 14 genes involved in calcium homeostasis are associated with the risk for colorectal adenoma. The researchers also wanted to determine whether intake of calcium and magnesium modified any such risks.

To do so, they utilized data from 1,818 cases and 3,992 controls enrolled in the Tennessee Colorectal Polyp Study. Of the 14 genes,KCNJ and SLC12A1 were found to modify the risk between calcium intake and adenomas.

Among the findings:

  • 52% of participants had a variant allele in one of the two genes, and 13% carried variant alleles in both genes.
  • In people with both gene variants, those the top tertile of calcium intake – consuming 1,300 mg a day or more – had a 69% lower risk of adenoma than people in the lowest tertile, who consumed less than 1,000 mg a day (P for trend=0.039).
  • In patients who had one gene variant, there was a 39% reduction in adenomas for those in the highest tertile compared with those in the lowest tertile (P for trend=0.046).

The risk for advanced or multiple adenomas were reduced by 89% among those with variants in both genes (P for trend=.01).

If confirmed, the findings suggest that patients who carry one or both variants should increase their calcium intake to at least 1,300 mg per day, either through diet or supplementation, Zhu said.

The findings may also “provide one possible explanation for the inconsistency in previous studies on calcium intake and colorectal abnormalities,” she said.

Further study will be needed to confirm the findings, commented Susan T. Mayne, PhD, of Yale University School of Public Health.

Mayne said the study emphasizes that “one size does not always fit all” when it comes to optimal nutrient intakes.

James R. Marshall, PhD, senior vice president of cancer prevention and population sciences at Roswell Park Cancer Institute in Buffalo, N.Y., agreed, pointing out that studies like this are needed to find biomarkers that can pinpoint those patients most likely to benefit from prevention strategies.

“Case-control studies raise possibilities that help to define which patients to include in future trials,” Marshall said.

Kathleen Struck, MedPage Today Senior Editor, contributed to this article.

The possibility that a supplement such as calcium may prove to be a useful chemoprevention agent is intriguing, but a single study is just a single study — worthy of more investigation. Share your thoughts and read what your colleagues are saying about calcium and colon cancer by clicking the Add Your Knowledge link at the bottom of this article. — Sanjay Gupta, MD

The authors reported no relevant financial disclosures.

Mayne and Marshall reported no relevant financial disclosures.

Primary source: American Association for Cancer Research

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Hold on. Mutations in Cancer do good.

Posted in BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, DNA repair, Loss of function gene, Next Generation Sequencing (NGS), tagged , , , , , , , on February 4, 2013| 1 Comment »

Reporter: Prabodh Kandala, PhD

Screen Shot 2021-07-19 at 6.21.55 PM

Word Cloud By Danielle Smolyar

A typical cancer cell has thousands of mutations scattered throughout its genome and hundreds of mutated genes. However, only a handful of those genes, known as drivers, are responsible for cancerous traits such as uncontrolled growth. Cancer biologists have largely ignored the other mutations, believing they had little or no impact on cancer progression.

But a new study from MIT, Harvard University, the Broad Institute and Brigham and Women’s Hospital reveals, for the first time, that these so-called passenger mutations are not just along for the ride. When enough of them accumulate, they can slow or even halt tumor growth.

The findings, reported in this week’sProceedings of the National Academy of Sciences, suggest that cancer should be viewed as an evolutionary process whose course is determined by a delicate balance between driver-propelled growth and the gradual buildup of passenger mutations that are damaging to cancer, says Leonid Mirny, an associate professor of physics and health sciences and technology at MIT and senior author of the paper.

Furthermore, drugs that tip the balance in favor of the passenger mutations could offer a new way to treat cancer, the researchers say, beating it with its own weapon — mutations. Although the influence of a single passenger mutation is minuscule, “collectively they can have a profound effect,” Mirny says. “If a drug can make them a little bit more deleterious, it’s still a tiny effect for each passenger, but collectively this can build up.”

Lead author of the paper is Christopher McFarland, a graduate student at Harvard. Other authors are Kirill Korolev, a Pappalardo postdoctoral fellow at MIT, Gregory Kryukov, a senior computational biologist at the Broad Institute, and Shamil Sunyaev, an associate professor at Brigham and Women’s.

Power struggle

Cancer can take years or even decades to develop, as cells gradually accumulate the necessary driver mutations. Those mutations usually stimulate oncogenes such as Ras, which promotes cell growth, or turn off tumor-suppressing genes such as p53, which normally restrains growth.

Passenger mutations that arise randomly alongside drivers were believed to be fairly benign: In natural populations, selection weeds out deleterious mutations. However, Mirny and his colleagues suspected that the evolutionary process in cancer can proceed differently, allowing mutations with only a slightly harmful effect to accumulate.

To test this theory, the researchers created a computer model that simulates cancer growth as an evolutionary process during which a cell acquires random mutations. These simulations followed millions of cells: every cell division, mutation and cell death.

They found that during the long periods between acquisition of driver mutations, many passenger mutations arose. When one of the cancerous cells gains a new driver mutation, that cell and its progeny take over the entire population, bringing along all of the original cell’s baggage of passenger mutations. “Those mutations otherwise would never spread in the population,” Mirny says. “They essentially hitchhike on the driver.”

This process repeats five to 10 times during cancer development; each time, a new wave of damaging passengers is accumulated. If enough deleterious passengers are present, their cumulative effects can slow tumor growth, the simulations found. Tumors may become dormant, or even regress, but growth can start up again if new driver mutations are acquired. This matches the cancer growth patterns often seen in human patients.

“Cancer may not be a sequence of inevitable accumulation of driver events, but may be actually a delicate balance between drivers and passengers,” Mirny says. “Spontaneous remissions or remissions triggered by drugs may actually be mediated by the load of deleterious passenger mutations.”

When they analyzed passenger mutations found in genomic data taken from cancer patients, the researchers found the same pattern predicted by their model — accumulation of large quantities of slightly deleterious mutations.

Tipping the balance

In computer simulations, the researchers tested the possibility of treating tumors by boosting the impact of deleterious mutations. In their original simulation, each deleterious passenger mutation reduced the cell’s fitness by about 0.1 percent. When that was increased to 0.3 percent, tumors shrank under the load of their own mutations.

The same effect could be achieved in real tumors with drugs that interfere with proteins known as chaperones, Mirny suggests. After proteins are synthesized, they need to be folded into the correct shape, and chaperones help with that process. In cancerous cells, chaperones help proteins fold into the correct shape even when they are mutated, helping to suppress the effects of deleterious mutations.

Several potential drugs that inhibit chaperone proteins are now in clinical trials to treat cancer, although researchers had believed that they acted by suppressing the effects of driver mutations, not by enhancing the effects of passengers.

In current studies, the researchers are comparing cancer cell lines that have identical driver mutations but a different load of passenger mutations, to see which grow faster. They are also injecting the cancer cell lines into mice to see which are likeliest to metastasize.

Ref:

Massachusetts Institute of Technology (2013, February 4). Some cancer mutations slow tumor growth. ScienceDaily. Retrieved February 4, 2013, from http://www.sciencedaily.com­/releases/2013/02/130204154011.htm

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Tumor Cells’ Inner Workings Predict Cancer Progression

Posted in Biological Networks, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, Cell Biology, Signaling & Cell Circuits, Gene Regulation, Genomic Expression, Hematology, Mutagenesis, Single Cell Genomics, Single-cell sequencing on July 29, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Using a new assay method to study tumor cells, researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center have found evidence of clonal evolution in chronic lymphocytic leukemia (CLL). The assay method distinguishes features of leukemia cells that indicate whether the disease will be aggressive or slow-moving, a key factor in when and how patients are treated.

The findings are published in the July 26, 2012 First Edition online issue of Blood.

The progression of CLL is highly variable, dependent upon the rate and effects of accumulating monoclonal B cells in the blood, marrow, and lymphoid tissues. Some patients are symptom-free for years and do not require treatment, which involves the use of drugs that can cause significant side effects and are not curative. In other patients, however, CLL is relatively aggressive and demands therapeutic intervention soon after diagnosis.

“Our study shows that there may not be a sharp dividing line between the more aggressive and less aggressive forms of CLL,” said Thomas J. Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research and senior author of the study. “Instead, it seems that over time the leukemia cells of patients with indolent disease begin to use genes similar to those that are generally used by CLL cells of patients with aggressive disease. In other words, prior to requiring therapy, the patterns of genes expressed by CLL cells appear to converge, regardless of whether or not the patient had aggressive versus indolent disease at diagnosis.”

Existing markers for aggressive or indolent disease are mostly fixed and have declining predictive value the longer the patient is from his or her initial diagnosis. When the blood sample is collected, these markers cannot reliably predict whether a CLL patient will need therapy soon, particularly when the patient has had the diagnosis of CLL for many years.

Kipps and colleagues studied thousands of genes, particularly those that code for proteins, in a group of 130 CLL patients with varying risks of disease progression. They identified 38 prognostic subnetworks of interacting genes and proteins that, at the time of sample collection, indicate the relative the aggressiveness of the disease and predict when the patient will require therapy. They confirmed their work using the method on two other, smaller CLL patient cohorts in Germany and Italy.

The subnetworks offer greater predictive value because they are based not on expression levels of individual genes or proteins, but on how they dynamically interact and change over time, influencing the course of the CLL and patient symptoms.

“In a sense, we looked at families rather than individuals,” said Kipps. “If you find in an interconnected family where most genes or proteins are expressed at higher levels, it becomes more likely that these genes and proteins have functional significance.”

He added that while the subnetworks abound in data, their complexity actually makes them easy to interpret and understand. “It’s like when you look out of a window and see the sky, clouds, trees, people, cars. You’re getting tremendous amounts of information that individually doesn’t tell you much. But when you look at the scene as a whole, you see patterns and networks. This work is similar. We’re taking all of the individual gene expression patterns and making sense of them as a whole. We’re more able to more clearly see how they control and regulate function.”

The findings help define how CLL — and perhaps other cancers — evolve over time, becoming more aggressive and deadly. “It’s as if each tumor has a clock which determines how frequently it may acquire the chance changes that make it behave more aggressively. Although the rates can vary, it appears that tumors march down similar pathways, which converge over time to a point where they become aggressive enough to require therapy.”

The study may alter how scientists think about CLL and how clinicians treat the disease: whether it is better to wait for later stages of the disease when tumor cells are more fragile and easier to kill, or treat early-stage indolent tumor cells aggressively, when they are fewer in number but harder to find and more resistant to therapy.

 

Abstract:

The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on two other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later time points prior to therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL.

 

Ref:

http://www.sciencedaily.com/releases/2012/07/120727154020.htm

http://bloodjournal.hematologylibrary.org/content/early/2012/07/26/blood-2012-03-416461

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All Cancer Cells Are Not Created Equal: Some Cell Types Control Continued Tumor Growth, Others Prepare the Way for Metastasis

Posted in Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, cancer metabolism, Circulating Tumor Cells (CTC), tumor microenvironment, tagged , , , , , , on May 17, 2012| 1 Comment »

Reporter: Prabodh Kandala, PhD

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Word Cloud By Danielle Smolyar

A study from Massachusetts General Hospital (MGH) researchers suggests that specific populations of tumor cells have different roles in the process by which tumors make new copies of themselves and grow. In their report in the May 15 issue of Cancer Cell, researchers identify a tumor-propagating cell required for the growth of a pediatric muscle tumor in a zebrafish model and also show that another, more-differentiated tumor cell must first travel to sites of new tumor growth to prepare an environment that supports metastatic growth.

“Most investigators have thought that tumor-propagating cells — what are sometimes called cancer stem cells — must be the first colonizing cells that travel from the primary tumor to start the process of local invasion and metastasis, but in this model, this is simply not the case,” says David Langenau, PhD, of the MGH Department of Pathology and Center for Cancer Research, who led the study. “Instead, the colonizing cells lack the ability to divide and instead prime newly infiltrated regions for the eventual recruitment of slow-moving cancer stem cells. It will be important to test how broadly this phenomenon is found in a diversity of animal and human cancers.”

Langenau’s team has long been using zebrafish to study rhabdomyosarcoma (RMS), an aggressive pediatric cancer. In embryonic zebrafish, RMS can develop within 10 days, and since the tiny fish are transparent at that stage, fluorescent markers attached to particular cellular proteins can easily be imaged. The current study used these properties to monitor how specific populations of tumor cells develop and their role in initiating new tumor growth.

Previous research from the MGH team had discovered that RMS cells expressing marker proteins also seen on muscle progenitor cells had significantly more tumor-propagating potential than did other tumor cells. Fluorescently labeling proteins associated with different stages of cellular differentiation revealed distinct populations of RMS cells in the zebrafish model. Cells expressing the progenitor cell marker myf5, were labeled green, and those expressing myogenin, a marker of mature muscle cells, were labeled red.

In a series of experiments, the research team confirmed that myf5-expressing RMS cells had powerful tumor-propagating potential, but the ability to visualize how tumor cells move in living fish produced a surprising observation. While myf5-expressing cells largely remained within the primary tumor itself, myogenin-expressing RMS cells easily moved out from the tumor, entering the vascular system and passing through usually impenetrable layers of collagen. Only after the more-differentiated but non-proliferative myogenin-expressing cells had colonized an area did the myf5-expressing tumor-propagating cells appear and start the growth a new tumor. Imaging the labeled tumor cells also revealed that different cellular populations tended to cluster in different areas of later-stage tumors.

“Our direct in-vivo imaging studies are the first to suggest such diverse cellular functions in solid tumors, based on differentiation and the propensity for self-renewal,” says Myron Ignatius, PhD, of MGH Pathology and Center for Cancer Research, the study’s first author. “I think we will find that this kind of division of labor is a common theme in cancer, especially given that the vast majority of cells within a tumor are not tumor-propagating cells. We suspect there will be molecularly defined populations that make niches for tumor-propagating cells, secrete factors to recruit vasculature and create boundaries to suppress immune cell invasion.”

Langenau adds, “Division of labor is a new and emerging concept in cancer research that we hope will lead to new targets for rationally designed therapies. In rhabdomyosarcoma it will be important to target both the tumor-propagating cells and the highly migratory colonizing cells for destruction — a major focus of ongoing studies in our group.” Langenau is an assistant professor of Genetics at Harvard Medical School and a principal faculty member at the Harvard Stem Cell Institute.

Additional co-authors author of the Cancer Cell article are Eleanor Chen, Adam Fuller, Ines Tenente Rayn Clagg, Sali Liu, Jessica Blackburn, MGH Pathology and Center for Cancer Research; Andrew Rosenberg, and Petur Neilsen, MGH Pathology; Natalie Elpek and Thorsten Mempel, MGH Center for Immunology and Inflammatory Diseases; and Corinne Linardic, Duke University Medical Center. The study was supported by grants from the National Institute of Health, the Alex’s Lemonade Stand Foundation, the Sarcoma Foundation of America, the American Cancer Society and the Harvard Stem Cell Institute.

http://www.sciencedaily.com/releases/2012/05/120515131756.htm

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