New Evidence For The Genetic Bases Of Liver Cancer

Main Category: Liver Disease / Hepatitis
Also Included In: Cancer / Oncology;??Genetics
Article Date: 03 Jul 2013 - 1:00 PDT Current ratings for:
New Evidence For The Genetic Bases Of Liver Cancer

The Asian Cancer Research Group (ACRG), an independent, not-for-profit company in collaboration with BGI, the world's largest genomics organization, and The University of Hong Kong (HKU), jointly announced the publication of findings from a study of recurrent mutations in hepatocellular carcinoma (HCC), one of the most deadly cancers worldwide, in the international journal Genome Research . The study provides new insights into potential therapeutic intervention strategies for this common form of liver cancer.

HCC is a primary malignancy of the hepatocytes, generally leading to death within 6-20 months after diagnosis. This type of cancer is more common in parts of Africa and Asia, where the patients with hepatitis B or C are at risk for liver cancer, even if they have not developed cirrhosis. HCC has limited treatment options such as surgical resection of the tumor at its early stage, and the molecular basis of its occurrence and development remains poorly understood.

In this study, researchers used whole genome sequencing (WGS) to survey a cohort of 88 matched HCC tumor and normal samples from Hong Kong for investigating alerted genes and the pathways implicated in HBV-associated HCC. They found that TP53 was the most commonly mutated tumor suppressor gene, accounting for 35.2% in the HCC cohort. Generally, the patients with tumors containing TP53 mutations exhibited poor survival.

The Wnt/β-Catenin signaling pathway is central for liver functions and is frequently abnormal activated in the carcinogenesis of HCC. Researchers in this study found β-catenin maybe the most frequently mutated oncogene. In addition to β-catenin, they found relative high mutation rates in genes in the JAK/STAT pathway, which may act as a major oncogenic driver in HCC tumor progression.

Hancheng Zheng, group leader of this project at BGI, said, "Liver cancer is intractable to nearly all currently available anti-cancer targeted therapies. Our findings in this study provide a better understanding of molecular basis of hepatocarcinogenesis and provide new clues to improving the diagnosis and treatment of liver cancer in the future."

"We detected a series of genes and pathways implicated in HBV-associated HCC using whole genome sequencing, which contribute to a better understanding of the tumor biology and targeted drug screening," said Dr. James Hardwick, Vice President of ACRG, and Director of Informatics & Analysis at Merck, "The ACRG was established to fuel research directed towards improving our understanding of cancers affecting Asian populations. By working together, we are able to generate important breakthroughs that can be transformed to better fight against liver cancer in the future."

"As clinicians, we are very excited about the several prevalent and actionable mutations identified from the study, including activating mutations of JAK1, which warrant testing several existing inhibitors for the treatment of the disease preclinically and clinically," said Dr. Ronnie Poon, Chair Professor and Chief, Division of Hepatobiliary and Pancreatic Surgery, The University of Hong Kong.

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Genetic signature of fatal Cancer identified

Main Category: Cancer / Oncology
Also Included In: Neurology / Neuroscience;??Genetics
Article Date: 05 Jun 2013 - 1:00 PDT Current ratings for:
Genetic Signature Of Deadly Brain Cancer Identified

A multi-institutional team of researchers have pinpointed the genetic traits of the cells that give rise to gliomas - the most common form of malignant brain cancer. The findings, which appear in the journal Cell Reports, provide scientists with rich new potential set of targets to treat the disease.

"This study identifies a core set of genes and pathways that are dysregulated during both the early and late stages of tumor progression," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., the senior author of the study and co-director of the Center for Translational Neuromedicine. "By virtue of their marked difference from normal cells, these genes appear to comprise a promising set of targets for therapeutic intervention."

As its name implies, gliomas arise from a cell type found in the central nervous system called the glial cell. Gliomas progress in severity over time and ultimately become highly invasive tumors known as glioblastomas, which are difficult to treat and almost invariably fatal. Current treatments, which include surgery, radiation therapy, and chemotherapy, can delay disease progression, but ultimately prove ineffective.

Cancer research has been transformed over the past several years by new concepts arising from stem cell biology. Scientists now appreciate that many cancers are the result of rogue stem cells or their offspring, known as progenitor cells. Traditional cancer therapies often do not prevent a recurrence of the disease since they may not effectively target and destroy the cancer-causing stem cells that lie at the heart of the tumors.

Gliomas are one such example. The source of the cancer is a cell found in the brain called the glial progenitor cell. The cells, which arise from and maintain characteristics of stem cells, comprise about three percent of the cell population of the human brain. When these cells become cancerous they are transformed into glioma stem cells, essentially glial progenitor cells whose molecular machinery has gone awry, resulting in uncontrolled cell division.

Goldman and his team have long studied normal glial progenitor cells. These cells produce glia, a category that includes both astrocytes - cells that support the function of neurons - and oligodendrocytes - cells that produces myelin, the fatty insulation that allows the long-distance conduction of neural impulses.

While Goldman's group's work has primarily focused on ways to use glial progenitor cells to treat neurological disorders such as multiple sclerosis, their understanding of the biology of these cells and mastery of the techniques required to sort, identify, and isolate these cells has also enabled them to explore the molecular and genetic changes that transform these cells into cancers.

Using human tissue samples representing the three principal stages of the cancer, the researchers were able to identify and isolate the cancer-inducing stem cells. Working with Goldman, lead authors Romane Auvergne, Ph.D. and Fraser Sim, Ph.D. then compared the gene expression profiles of these cancer stem cells to those of normal glial progenitor cells. The objective was to both pinpoint the earliest genetic changes associated with cancer formation and identify those genes that were unique to the cancer stem cells and were expressed at every stage of disease progression.

Out of a pool over 44,000 tested genes and sequences, the scientists identified a small set of genes in the cancerous glioma progenitor cells that were over-expressed at all stages of malignancy. These genes formed a unique "signature" that identified the tumor progenitor cells and enabled the scientists to define a corresponding set of potential therapeutic targets present throughout all stages of the cancer.

"One of the key things you are looking for in drug development in cancer is a protein or gene that is over-expressed, so that you can attempt to achieve therapeutic benefit by inhibiting it," said Goldman.

The researchers chose to test this hypothesis by targeting one such gene, called SIX1, which was highly overexpressed in the glioma progenitor cells. While this particular gene is active in the early development of the nervous system, it had not been observed in the adult brain before. However, SIX1 signaling has been associated with breast and ovarian cancer, raising the possibility of its contribution to brain cancer as well. This turned out to indeed be the case. When the researchers blocked - or knocked down - the expression of this gene, the tumor cells ceased growing, and implanted tumors shrank.

"This study gives us a blueprint to develop new therapies," said Goldman. "We can now devise a strategy to systematically and rationally analyze - and eliminate - glioma stem and progenitor cells using compounds that may selectively target these cells, relative to the normal glial progenitors from which they derive. By targeting genes like SIX1 that are expressed at all stages of glioma progression, we hope to be able to effectively treat gliomas regardless of their stage of malignancy. And by targeting the glioma-initiating cells in particular, we hope to lessen the likelihood of recurrence of these tumors, regardless of the stage at which we initiate treatment."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Additional authors include Su Wang, Devin Chandler-Militello, Jaclyn Burch, Yazan Al Fanek, Danielle Davis, Abdellatif Benraiss, Mahlon Johnson, and Kevin Walter with URMC, Pragathi Achanta and Alfredo Quinones-Hinojosa with the Johns Hopkins University School of Medicine, Heidi Ford with the University of Colorado Denver, and Sridaran Natesan with Sanofi-Aventis Pharmaceuticals. Sim is now at the University at Buffalo School of Medicine and Biomedical Sciences. The study was supported with grants from the National Institute of Neurological Disorders and Stroke, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the New York Stem Cell Research Board, the James S. McDonnell Science Foundation, and Sanofi-Aventis Pharmaceuticals.
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Under-Use Of Genetic Testing Puts Health Of Entire Families At Risk

Main Category: Genetics
Also Included In: Cancer / Oncology;??Colorectal Cancer;??Breast Cancer
Article Date: 11 Jun 2013 - 0:00 PDT Current ratings for:
Under-Use Of Genetic Testing Puts Health Of Entire Families At Risk

A new study of the use of genetic testing for cancer-causing mutations in affected families in France has found that its take-up is very low. Professor Pascal Pujol, Head of the Cancer Genetics Department, Montpellier University Hospital, Montpellier, France told the annual conference of the European Society of Human Genetics that analysis of data from the French National Cancer Institute covering the years 2003 to 2011 showed that, although there had been a steady increase in tests performed for the breast and ovarian cancer-causing mutations BRCA1 and BRCA2, this was not the case with the MMR mutation, implicated in Lynch syndrome (a form of colorectal cancer). Only a third of relatives of individuals with either mutation underwent genetic testing themselves.

"Given that such testing can provide many options to enable individuals to manage their cancer risk, it is vital to encourage awareness and acceptance among both the public and medical professionals", he will say. "For example, removal of the ovaries in women over 40 years old who carry a BRCA mutation decreases their overall cancer mortality by 20% and prophylactic mastectomy can reduce the chances of breast cancer in women carrying such a mutation by around 90%. Those who are unwilling to undergo prophylactic surgery can benefit from increased surveillance, with regular MRI (magnetic resonance imaging) scans. For familial colon cancer, screening by colonoscopy has been shown to decrease mortality. It is therefore regrettable that so few people seem to be aware of the benefits of genetic testing in families with a history of breast, ovarian, or colorectal cancer."

Professor Pujol and colleagues from cancer centres across France analysed 240134 consultations and 134652 genetic tests from patients referred for a predisposition to breast or colorectal cancer. They found a substantial increase in tests for BRCA1/2 - from 2095 a year in 2003 to 7393 in 2011 - but for MMR mutations the increase was tiny - from 1144 to 1635 a year over the same period.

Mutations in BRCA1/2 genes are thought to be responsible for about 5% of all cases of breast and ovarian cancer. A woman with such a mutation has a risk of up to 87% of having breast cancer before she reaches the age of 80, as opposed to a risk of 8% in the general population. Such cancers are diagnosed at an average age of 43, as opposed to 60 in the general population, and are often more aggressive. In the case of ovarian cancer, a woman carrying a BRCA1 mutation has a risk of ovarian cancer of up to 63%.

Individuals with Lynch syndrome, or hereditary nonpolyposis colorectal cancer, have a 45% risk of developing colorectal cancer by the age of 70, and women with the syndrome are at increased risk of endometrial and ovarian cancers.

"While the increase in BRCA testing is encouraging, it is far from optimal. And the uptake of MMR testing for Lynch syndrome - responsible for 5% of all colorectal cancers - is frankly disappointing", says Professor Pujol. "And of course, positive test results may have implications for other family members.

"While we have only studied the situation in France, we believe that our findings would be likely to be replicated in many other countries across the world. It is extremely worrying that such a simple test, which has the potential to spare whole families from devastating illness, is being so under-used. We urgently need a major programme of awareness among all those concerned, involving medical education and training, information programmes for patients and their families, public health campaigning, and improved genetic counselling," he concluded.

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4 New Genetic Risk Factors Identified For Testicular Cancer

Main Category: Cancer / Oncology
Also Included In: Men's Health;??Genetics
Article Date: 14 May 2013 - 1:00 PDT Current ratings for:
4 New Genetic Risk Factors Identified For Testicular Cancer

A new study looking at the genomes of more than 13,000 men identified four new genetic variants associated with an increased risk of testicular cancer, the most commonly diagnosed type in young men today. The findings from this first-of-its-kind meta-analysis were reported online in Nature Genetics by researchers at the Perelman School of Medicine at the University of Pennsylvania.

The discovery of these genetic variations - chromosomal "typos," so to speak - could ultimately help researchers better understand which men are at high risk and allow for early detection or prevention of the disease.

"As we continue to cast a wider net, we identify additional genetic risk factors, which point to new mechanisms for disease," said Katherine L. Nathanson, MD, associate professor in the division of Translational Medicine and Human Genetics within the department of Medicine. "Certain chromosomal regions, what we call loci, are tied into testicular cancer susceptibility, and represent a promising path to stratifying patients into risk groups - for a disease we know is highly heritable."

Tapping into three genome-wide association studies (GWAS), the researchers, including Peter A. Kanetsky, PhD, MPH, an associate professor in the department of Biostatistics and Epidemiology, analyzed 931 affected individuals and 1,975 controls and confirmed the results in an additional 3,211 men with cancer and 7,591 controls. The meta-analysis revealed that testicular germ cell tumor (TGCT) risk was significantly associated with markers at four loci - 4q22, 7q22, 16q22.3, and 17q22, none of which have been identified in other cancers. Additionally, these loci pose a higher risk than the vast majority of other loci identified for some common cancers, such as breast and prostate.

This brings the number of genomic regions associated with testicular cancer up to 17 - including eight new ones reported in another study in this issue of Nature Genetics.

Testicular cancer is relatively rare; however, incidence rates have doubled in the past 40 years. It is also highly heritable. If a man has a father or son with testicular cancer, he has a four-to six-fold higher risk of developing it compared to a man with no family history. That increases to an eight-to 10-fold higher risk if the man has a brother with testicular cancer.

Given this, researchers continue to investigate genetic variants and their association with cancer.

In 2009, Dr. Nathanson and colleagues uncovered variation around two genes - KITLG and SPRY4 - found to be associated with an increased risk of testicular cancer. The two variants were the first striking genetic risk factors found for this disease at the time. Since then, several more variants have been discovered, but only through single GWAS studies.

"This analysis is the first to bring several groups of data together to identify loci associated with disease," said Dr. Nathanson, "and represent the power of combining multiple GWAS to better identify genetic risk factors that failed to reach genome-wide significance in single studies."

The team also explains how the variants associated with increased cancer risk are the same genes associated with chromosomal segregation. The variants are also found near genes important for germ cell development. These data strongly supports the notion that testicular cancer is a disorder of germ cell development and maturation.

"TGCT is unique in that many of the loci are very good biological candidates due to their role in male germ cell development," said Dr. Nathanson. "Disruptions in male germ cell development lead to tumorigenesis, and presumably also to infertility. These conditions have been linked before, epidemiologically, and genes implicated in both of our prior studies, but this study reinforces that connection."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. This study was supported in part by Intramural Research Program of the National Cancer Institute and the National Institutes of Health grant (R01CA114478).
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Genetic Differences May Influence the Severity of Joint Pain Among Breast Cancer Patients Taking Aromatase Inhibitors

Aromatase inhibitor-associated arthralgia (AIAA)? is a major side effect in breast cancer survivors, producing joint pain so severe that as many as ten percent of women discontinue their therapy prematurely while undergoing treatment with these lifesaving drugs. New research presented by investigators from the University of Pennsylvania’s Abramson Cancer Center at the 2010 meeting of the American Society of Clinical Oncology reveals a possible genetic basis for why these side effects occur and shows promise for treating these symptoms without interfering with the drugs’ efficacy. Additional research will also be presented shedding light on the physical and psychological factors that influence women’s decisions to stop taking the drugs.

Jun Mao, MD, MSCE, an assistant professor of Family Medicine and Community Health who heads the Abramson Cancer Center’s integrative oncology program, led a team that studied individual genetic variations that could potentially influence both the onset and the severity of AIAA.[1] His team studied 390 postmenopausal women with Stage 0 to III breast cancer receiving adjuvant therapy with aromatase inhibitors who reported joint pain related to their drug therapy.? They found that among this group, women carrying at least one copy of a “7-repeat” genetic variant in the aromatase enzyme (CYP19A1, the target of aromatase inhibitors) had a lower chance of developing AAIA than those with at least one “8-repeat” allele of the same gene. Having at least one copy of a specific IL-6 haplotype was also correlated with increased pain severity, while the presence of a different variant of that gene was associated with decreased pain.? Both these findings support previous research that indicates an important role for host estrogen metabolism and inflammation in causing AIAA.

“Due to genetic differences, women respond differently to aromatase inhibitors with regard to estrogen levels and inflammatory processes, and as a result, some women are more likely to have this pain or have more severe pain,” says Angela DeMichele, MD, MSCE, an associate professor of Hematology/Oncology and Epidemiology and Biostatistics, and a co-author on all three of the studies. “There are millions of women receiving AIs, as many as 50 percent of them experience some level of arthralgia, and up to 10 percent discontinue their treatment prematurely, so this is a significant issue.”

The investigators say that as more breast cancer patients become breast cancer survivors, clinicians must become more knowledgeable about the quality of life issues impacting women after they end active treatment for their cancers. The new findings are key to identifying which women may be at risk of problems like arthralgia—and then, Mao says, to developing more targeted interventions at both the physical and psychological levels.

The multidisciplinary team is also looking at issues related to clinician-patient communication, exercise, and co-factors such as arthritis or fibromyalgia that can increase pain and disability in order to keep more women on their treatment regimen. Mao, who is also a licensed physician acupuncturist, has begun a clinical trial examining the effectiveness of acupuncture for aromatase inhibitor associated arthralgia as part of conventional breast cancer survivorship care. These efforts are part of the Abramson Cancer Center’s comprehensive Wellness After Breast Cancer program.

“We believe that proactively informing women about the possibility that their breast cancer treatment may cause arthralgia and then intervening early is probably important to keeping them on these potentially life-saving cancer treatments,” Mao says. “When they are not prepared, or become frustrated because they didn’t know this could happen to them, they are far more likely to make the decision to stop treatment. Some studies have suggested that women with the most severe symptoms are those with the most complete blockage of aromatase. We want to do everything we can to assure that the women most likely to benefit from therapy don’t end it too soon because they are experiencing pain related to their treatment.”

In a related study, University of Pennsylvania researchers surveyed 300 breast cancer survivors to assess the impact of AIAA on upper and lower extremity functioning.[2] They found that women with AIAA had greater impairment of both upper and lower extremities than those who did not experience these symptoms. As many as 29 percent of participants reported that the pain limited their ability to perform their normal activities.

In a third study, Carrie Stricker, PhD, RN, clinical assistant professor of Nursing and an oncology nurse practitioner, led the team of researchers in surveying 490 postmenopausal, non-metastatic breast cancer patients to assess the factors that influenced their stopping AI therapy prematurely.[3]? This is one of only a few studies to analyze the rates at which women discontinue AI therapy and the variables that predict their decision to do so, and the only designed to evaluate patient-reported reasons for ending AI treatment. The study found that 7 percent of the patients studied had discontinued their AI treatment early, at a mean of 15.7 months from the beginning of treatment. The most significant predictors for stopping therapy were a previous history of taking tamoxifen, which can also cause arthralgia and other symptoms; having other inflammatory conditions such as arthritis; communication about difficulties with taking AIs, and being married. Patients who stopped AI treatment early cited side effects as the main reason, with arthralgia being the most common complaint. Effects on bone, hot flashes, and cognitive effects were also named as reasons for cessation of therapy.

“These data suggest that we can develop a profile of the women who are most likely to make the decision to terminate their AI therapy prematurely, and if we can do that, we can design better supportive interventions for these women and incorporate them into our clinical practice,” DeMichele says. “This information, derived directly from the patients themselves, reinforces our understanding that assessing and managing the side effects of cancer therapy, including joint pain, is critical to the overall success we can achieve in managing the disease itself.”

References:

[1] Mao J, Su I, Feng R et al. Genetic variation in CYP19A1 and interleukin-6 and aromatase inhibitor-associated arthralgia in breast cancer survivors. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 526.

[2] Stricker CT, Palmer SC, DeMichele A, Mao J. Understanding premature discontinuation of aromatase inhibitor (AI) therapy in postmenopausal breast cancer survivors. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 6073.

[3] Friedman CF, Bruner D, Xie S et al. Functional disability and aromatase inhibitor-associated arthralgia in breast cancer survivors. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract 9156.

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