Many patients who have genetic testing for Lynch syndrome, a hereditary predisposition to colon cancer, receive the inconclusive result ‘variants of uncertain clinical significance.’ This can be a problem, as people with Lynch syndrome have a much higher probability to develop colon cancer, and often develop colon cancer at an earlier age than is common among the general population; consequently, they need to begin screening at a much younger age.
Now, between two-thirds and three-fourths of these genetic variants can be classified into categories that indicate the most appropriate screening and treatment guidelines, according to two complementary papers recently published. The two papers, both co-authored by Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah, provide a model that could help physicians as they assess their patient’s risk to develop cancer.
According to the American Cancer Society, about 143,460 new cases of colon cancer will be diagnosed in the United States this year. The National Cancer Institute estimates that two to four percent of all colon cancer is attributable to Lynch syndrome.
Mutations in mismatch repair genes, which proof-read DNA to correct genetic typos that occur during the replication process, are known to be the cause of the syndrome. ‘Some people in families with Lynch syndrome have already known mutations, and a small number of missense substitutions have also been classified as pathogenic,’ said Tavtigian. ‘But a fair number have other missense substitutions for which the clinical significance could not be determined, creating uncertainty concerning proper screening and treatment for patients and physicians alike.’
The first of the two studies reported on standardising several already available computer programs that grade the severity of missense substitutions (at the genomic level, these mutations affect only a single structural unit of DNA rather than an entire gene; at the protein level, they affect only a single amino acid rather than the entire protein). The second describes how clinical data concerning the tumours, family history, and other factors were combined with that initial information about severity. Taken together, the procedures described in the two papers allow previously unclassified genetic variations to be assessed for the level of risk they pose in colon cancer development.
‘Using these tools, we can evaluate any particular missense substitution and come up with a percentage indicating the probability that it is pathogenic,’ said Tavtigian. ‘I’m very careful to avoid saying pathogenic or neutral as an either-or statement. With missense substitutions, I don’t believe in a binary classification.’ A scale developed by his team in 2008 indicates the appropriate level of clinical action for a given percentage of risk, he adds. Huntsman Cancer Institute

Researchers at Case Western Reserve University School of Medicine have discovered a mutant form of the gene, Chk1, that when expressed in cancer cells, permanently stopped their proliferation and caused cell death without the addition of any chemotherapeutic drugs. This study illustrates an unprecedented finding, that artificially activating Chk1 alone is sufficient to kill cancer cells.
‘We have identified a new direction for cancer therapy and the new direction is leading us to a reduction in toxicity in cancer therapy, compared with chemotherapy or radiation therapy,’ said Dr. Zhang, assistant professor, Department of Pharmacology at the School of Medicine, and member of the university’s Case Comprehensive Cancer Center. ‘With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.’
While studying the basic mechanisms for genome integrity, Dr. Zhang’s team unexpectedly discovered an active mutant form of human Chk1, which is also a non-natural form of this gene. This mutation changed the protein conformation of Chk1 from the inactive form into an active form. Remarkably, the research team discovered that when expressed in cancer cells, this active mutant form of Chk1 permanently stopped cancer cell proliferation and caused cell death in petri dishes even without the addition of any chemotherapeutic drugs.
The biggest advantage of this potential strategy is that no toxic chemotherapeutic drug is needed to achieve the same cancer killing effect used with a combination of Chk1 inhibitors and chemotherapeutic drugs.
Cells respond to DNA damage by activating networks of signalling pathways, termed cell cycle checkpoints. Central to these genome pathways is the protein kinase, called Chk1. Chk1 facilitates cell survival, including cancer cells, under stressful conditions, such as those induced by chemotherapeutic agents, by placing a temporary stop on the cell cycle progression and co-ordinating repair programs to fix the DNA errors.
It has long been suggested that combining Chk1 inhibition with chemotherapy or radiotherapy should significantly enhance the anticancer effect of these therapies. This idea has serves as the basis for multiple pharmaceutical companies searching for potential Chk1 inhibitors that can effectively combine with chemotherapy in cancer therapy. To date, no Chk1 inhibitor has passed the clinical trial stage III . This led Dr. Zhang’s team to look for alternative strategies for targeting Chk1 in cancer therapy.
Future research by Dr. Zhang and his team will consider two possible approaches to artificially activating Chk1 in cancer cells. One possibility is to use the gene therapy concept to deliver the active mutant form of Chk1 that the team discovered, into cancer cells. The other is to search for small molecules that can induce the same conformational change of Chk1, so that they can be delivered into cancer cells to activate Chk1 molecules. The consequence of either would be permanent cell proliferation inhibition and cancer. EurekAlert

Could one test be used for a range of cancers?
Targeting just one chemical inside cancerous cells could one day lead to a single test for a broad range of cancers, researchers say.
The same system could then be used to deliver precision radiotherapy. Scientists told the National Cancer Research Institute conference they had been able to find breast cancer in mice weeks before a lump had been detected.
The same target chemical was also present in cancers of the lung, skin, kidney and bladder, they said.
The team, at the Gray Institute for Radiation Oncology and Biology at Oxford University, were looking for a protein, called gamma-H2AX, which is produced in response to damaged DNA. This tends to be one of the first steps on the road to a cell becoming cancerous.
The scientists used an antibody that is the perfect partner to gamma-H2AX and able to seek it out in the body.
This was turned into a cancer test by attaching small amounts of radioactive material to the antibody. If the radiation gathered in one place it would be a sign of a potential tumour. The researchers trialled the test on genetically modified mice, which are highly susceptible to forming tumours.
Prof Katherine Vallis said lumps could be felt when the mice were about 120 days old, but ‘we detected changes prior to that at 90 to 100 days – before a tumour is clinically apparent’.
She told the BBC that gamma-H2AX was a ‘fairly general phenomenon’ and it ‘would be the dream’ to develop a single test for a wide range of cancers. However this is still at a very early stage.
Adding more radiation to the antibody could convert the test to a treatment.
Prof Vallis said ‘it is attracted to DNA damage’, where it then delivers a dose of radiation, causing more damage and attracting even more antibodies – it is a ‘self-amplifying system’. Eventually the doses of radiation should do so much damage to the cancerous cells that they would be killed.
She said: ‘This early research reveals that tracking this important molecule could allow us to detect DNA damage throughout the body.
‘If larger studies confirm this, the protein could provide a new route to detect cancer at its very earliest stage – when it is easier to treat successfully.’ BBC

Children with HIV have a 2.5 fold increased risk of atherosclerosis, according to research presented at EUROECHO and other Imaging Modalities 2012. Antiretroviral treatment, lipid lowering drugs and prevention with healthy lifestyles are needed to prevent early death from cardiovascular disease.
EUROECHO and other Imaging Modalities 2012 is the annual meeting of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the European Society of Cardiology (ESC).
Antiretroviral treatment is prolonging the lives of HIV patients, who no longer die prematurely from the infection. But the treatment is not a cure, and the virus remains in the body.
‘The infection makes the body fight for its life, so the immune system is always activated and there is chronic inflammation,’ said Dr Talia Sainz Costa, principal investigator of the study and a paediatrician from Madrid, Spain.
In addition, many antiretroviral drugs increase bad (LDL) cholesterol and lower good (HDL) cholesterol. Dr Sainz Costa said:
‘Children with HIV will have high cholesterol for a long period and on top of that the virus causes chronic inflammation – both are bad for the arteries.’
Patients with HIV die 10 years prematurely from non-AIDS disease which includes cardiovascular diseases, cancer, liver and renal diseases.
‘This is especially important for children because they have been living with HIV since birth or even before,’ said Dr Sainz Costa. ‘By the time they are 50 years old they will have accumulated more toxicity from the treatment and more secondary effects from the infection and will be at an even greater risk of heart attacks and other complications.’
The present study aimed to discover whether children and adolescents already have early atherosclerosis damage. Carotid intima-media thickness (IMT), a marker of atherosclerosis, was measured using echocardiography in 150 children and adolescents with HIV and 150 age and sex matched healthy controls.
The researchers found that 17% of the HIV group were smokers compared to 11% of the control group. Dr Sainz Costa said:
‘Smoking levels in adolescents in Spain are known to be high. The even higher levels in the HIV group are probably related to low socio-economic status and very complex social/family backgrounds.’
After adjustment for age, sex, BMI and smoking status, HIV was independently associated with thicker IMT (p=0.005). Children and adolescents had a 2.5 fold increased risk of higher IMT due to HIV. Dr Sainz Costa said:
‘Our study shows that children and adolescents with HIV have arteries that are more rigid and less elastic, which means that the process of atherosclerosis has begun and they have increased risk of an infarct in the future.’
The researchers also found that frequencies of activated T CD4+ cells were higher among HIV-infected children and young adults (p=0.002). ‘This shows that the immune system is more active,’ said Dr Sainz Costa.
They concluded that clinicians need to take cardiovascular prevention more seriously in children and adolescents with HIV, while continuing to treat the HIV infection. Dr Sainz Costa said: ‘Cardiovascular disease has already put down roots in children and adolescents with HIV and we need to take preventive measures at this early stage. We should be more aggressive in treating their high cholesterol with medication – this practice is common in adults but rare in children.’ She added:
‘We also need to be stricter about healthy lifestyle advice. Many children and adolescents with HIV come from families with low socio-economic status and are more prone to smoking, poor diet and inactivity. This age group also struggles with adherence to medication which is another worry, but we should not let this decrease our efforts to prevent future complications.’
Dr Sainz Costa concluded: ‘HIV research is investigating ways to control the inflammation and immune activation with agents such as probiotics, aspirin and corticoids. In the meantime clinicians need to focus on ensuring their young patients with HIV take the antiretroviral treatment, take lipid lowering drugs when necessary, and adopt healthier lifestyles.’ European Society of Cardiology

For the millions of people world-wide with type 1 diabetes who cannot produce sufficient insulin, the potential to transplant insulin-producing cells could offer hope for a long-term cure. The discovery of a marker to help identify and isolate stem cells that can develop into insulin-producing cells in the pancreas would be a critical step forward.
Pancreatic stem cells, the precursors of insulin-producing cells, have not yet been identified in humans or animals, and there is much debate about where they may reside. Ivka Afrikanova, Ayse Kayali, Ana Lopez, and Alberto Hayek, University of California, San Diego, CA, have identified a biochemical marker—stage-specific embryonic antigen 4 (SSEA4)—that they propose can be used to identify and purify human pancreatic stem cells. The article ‘Is Stage-Specific Embryonic Antigen 4 a Marker for Human Ductal Stem/Progenitor Cells’ reports that when grown in culture with high levels of glucose and B27, these SSEA4+ stem cells can differentiate into insulin-producing pancreatic cells. EurekAlert