The deletion variant of the ADRA2B gene and the genetic predisposition to focus on the negative

October 17, 2013 – This morning, while commuting (a one and a half hour train ride) not only was I noticing all those stoned and negatively charged early morning faces of my fellow commuters but also I stumbled upon the following fantastic little article on PsyBlog, which explains it all. And yes, I am definitively not a carrier of the deletion variant of ADRA2B. I just imagined how a homozygote individual (i.e. ADRA2Bdel / ADRA2B del) would possibly cope with the world early in the morning. Go on reading the article below (in italics):

Some people are genetically predisposed to spot negative events automatically, according to a new study published in Psychological Science (Todd et al., 2013). A gene called ADRA2B seems to cause people to take particular note of negative emotional events. The study’s lead author, Professor Rebecca Todd explained:

“This is the first study to find that this genetic variation can significantly affect how people see and experience the world. The findings suggest people experience emotional aspects of the world partly through gene-coloured glasses — and that biological variations at the genetic level can play a significant role in individual differences in perception.”

The study used a phenomenon called ‘attentional blink‘ and involved participants looking at a series of positive, negative and neutral emotional words. Those who had the ADRA2b gene variant were more likely to perceive the negative emotional words than those without it. 

Positive emotion words, though, were perceived by those with and without the gene to the same degree.

Of course, we all need to spot very strong emotional stimuli around us–like a loved one in pain or anger and aggression in others–but paying too much attention to negative events can obviously make us unhappy. Not only is the gene linked to differences between people in their attention, but also to memory. People with the gene likely also find negative events are enhanced in their memories.

It may mean that people with the gene are more likely to suffer from uncomfortable flashbacks to negative memories or even posttraumatic stress disorder. Statistically, around 50% of Caucasians have the ADRA2Bdel gene variant, but the rates are much lower in other ethnicities.

As with many genes, though, they interact with the environment: their effect on our individual psychology is partly determined by our upbringing, those around us and how we choose to think and act. Just because there is a gene that influences our starting point, that doesn’t stop us having some control over where we end up.

FDA approves new treatment for a type of late-stage lung cancer. Companion test also approved to identify appropriate patients

July 18, 2013 – The U.S. Food and Drug Administration (FDA) very recently approved Gilotrif (afatinib) for patients with late stage (metastatic) non-small cell lung cancer (NSCLC) whose tumors express specific types of epidermal growth factor receptor (EGFR) gene mutations, as detected by an FDA-approved test.

Lung cancer is the leading cause of cancer-related death among men and women. According to the National Cancer Institute, an estimated 228,190 Americans will be diagnosed with lung cancer, and 159,480 will die from the disease this year. About 85 percent of lung cancers are NSCLC, making it the most common type of lung cancer. EGFR gene mutations are present in about 10 percent of NSCLC, with the majority of these gene mutations expressing EGFR exon 19 deletions or exon 21 L858R substitution.

Gilotrif is a tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients whose tumors express the EGFR exon 19 deletions or exon 21 L858R substitution gene mutations. Gilotrif is being approved concurrently with the therascreen EGFR RGQ PCR Kit, a companion diagnostic that helps determine if a patient’s lung cancer cells express the EGFR mutations.

“Today’s approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Gilotrif is the second drug approved this year for patients with untreated metastatic NSCLC whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations.”

In May, the FDA approved Tarceva (erlotinib) for first-line treatment of patients with NSCLC. Tarceva’s new indication was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic to identify patients with tumors having the EGFR gene mutations.

“The approval of companion diagnostic tests and drugs are important developments in oncology, as they help us bring safe and effective treatments to patients who need them,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

The FDA’s approval of the therascreen EGFR RGQ PCR Kit is based on data from the clinical study used to support Gilotrif’s approval. Tumor samples from NSCLC participants in the clinical trial helped to validate the test’s use for detecting EGFR mutations in this patient population.

Gilotrif’s safety and effectiveness were established in a clinical study of 345 participants with metastatic NSCLC whose tumors harbored EGFR mutations. Participants were randomly assigned to receive Gilotrif or up to six cycles of the chemotherapy drugs pemetrexed and cisplatin.

Participants receiving Gilotrif had a delay in tumor growth (progression-free survival) that was 4.2 months later than those receiving chemotherapy. There was no statistically significant difference in overall survival.

Common side effects of Gilotrif include diarrhea, skin breakouts that resemble acne, dry skin, itching (pruritus), inflammation of the mouth, skin infection around the nails (paronychia), decreased appetite, decreased weight, inflammation of the bladder (cystitis), nose bleed, runny nose, fever, eye inflammation and low potassium levels in the blood (hypokalemia). Serious side effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation and liver toxicity.

The FDA reviewed Gilotrif under its priority review program, which provides an expedited review for drugs that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products.

Gilotrif is marketed by Ridgefield, Conn.-based Boehringer Ingelheim Pharmaceuticals, Inc. The therascreen EGFR RGQ PCR Kit is manufactured by QIAGEN Manchester Ltd., based in the United Kingdom. The cobas EGFR Mutation Test is manufactured by the Roche Molecular Systems in Pleasanton, Calif., and Tarceva is co-marketed by California-based Genentech, a member of the Roche Group, and OSI Pharmaceuticals of Farmingdale, N.Y.

For more information:
FDA: Office of Hematology and Oncology Products
FDA: CDRH Office of In Vitro Diagnostics and Radiological Health
FDA: Approved Drugs: Questions and Answers
FDA: Drug Innovation

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Dabrafenib [Tafinalar] and Trametinib [Mekinist] Approved for BRAF V600 Mutated Metastatic Melanoma

May 30, 2013 – From a Medscape News Release we learn today that two new drugs have been approved by the US Food and Drug Administration (FDA) for use in certain patients with metastatic or unresectable melanoma, along with a diagnostic test to identify patients who are suitable for treatment.

The new products, Dabrafenib [Tafinalar] and Trametinib [Mekinist], were both developed by GlaxoSmithKline. Both are orally available tablets, but they have slightly different mechanisms of action.

Dabrafenib [Tafinalar]  acts as a BRAF inhibitor and is approved for use in patients with melanoma whose tumors express the BRAF V600E gene mutation. It is seen as being a next-generation product but is in the same class as the first BRAF inhibitor to reach the market, Vemurafenib [Zelboraf] (Genentech).

Trametinib [Mekinist] has a related but slightly different mechanism and acts as a mitogen-activated, extracellular signal-regulated kinase inhibitor (MEK inhibitor). It is the first drug in this class to be approved and is indicated for use in patients with whose tumors express the BRAF V600E or V600K gene mutations.

Approximately half of melanomas arising in the skin have a BRAF gene mutation, the FDA notes in its approval notice. Alongside the new drugs, the agency also approved a genetic test, the THxID BRAF test, a companion diagnostic developed in collaboration with bioMérieux that will help determine wither a patient’s melanoma cells have the V600E or V600K mutation in the BRAF gene.

Melanoma is the leading cause of death from skin disease, the FDA adds. The National Cancer Institute estimates 76,690 Americans will be diagnosed with melanoma and 9480 will die from the disease in 2013.

Clinical Trial Data

Dabrafenib [Tafinalar]  was approved on the basis of data from the BREAK 3 study, conducted in 250 patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. It showed that in such patients, Dabrafenib [Tafinalar]  significantly improved the median progression-free survival compared with chemotherapy with dacarbazine (5.1 vs 2.7 months; P < .0001). These results were published in July 2012 issue of the Lancet (2012;380:358-365).

The FDA notes that the most serious adverse effects reported in patients receiving Dabrafenib [Tafinalar] included an increased risk for cutaneous squamous cell carcinoma, fevers that may be complicated by hypotension, severe rigors, dehydration, kidney failure, and increased blood sugar levels requiring changes in diabetes medication or the need to start medicines to control diabetes.

The most common adverse effects reported in patients receiving Dabrafenib [Tafinalar]  included hyperkeratosis, headache, fever, joint pain, noncancerous skin tumors, hair loss, and hand–foot syndrome.

The pivotal study for Trametinib [Mekinist], the METRIC study, was a little different in that it was conducted in 322 patients who had already tried a prior regimen of chemotherapy. In this study, compared with chemotherapy, Trametinib [Mekinist] significantly improved progression-free survival as well as overall survival. The results were published in the New England Journal of Medicine.

The FDA notes that the most serious adverse effects reported in patients receiving Trametinib [Mekinist]  included heart failure, lung inflammation, skin infections, and loss of vision. Common adverse effects included rash, diarrhea, tissue swelling (peripheral edema), and skin breakouts that resemble acne.

The agency also noted that women of childbearing years should be advised that Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  carry the potential to cause fetal harm. Men and women should also be advised that both drugs also carry the potential to cause infertility.

Being Investigated in Combination

Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  have been approved for use as monotherapy, and not as a combination treatment, the FDA has emphasized. However, there is a lot of interest from clinicians in using both drugs together, and indeed the manufacturer is conducting a clinical trial with the combination.

Preliminary results from a clinical trial with the combination suggest that use of the 2 drugs together resulted in less toxicity, and specifically in fewer secondary skin cancers, than has been seen with  Vemurafenib [Zelboraf]  used alone.

GlaxoSmithKline is now conducting a phase 3 study (known as COMBI-AD) of the combination of Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  in patients with BRAF V600 melanoma that has been completely removed by surgery. Such patients are at high risk for relapse, and the combination of drugs is being tested to see whether it can delay or prevent the recurrence of melanoma, the company noted.

Problem: Responses Are Short-lived

The new Dabrafenib [Tafinalar]  appears to be similar to the already-marketed Vemurafenib [Zelboraf], but there are important differences between the 2 BRAF inhibitors in their toxicity profiles, noted Kim Margolin, MD, from the Seattle Cancer Care Alliance in Washington..

Skin toxicities, particularly the emergence of low-grade squamous cancers and keratoacanthomas, which occurred in a substantial number of patients taking Vemurafenib [Zelboraf], appear to be quite unusual with Dabrafenib [Tafinalar], Dr. Margolin noted. However, a systemic “pyrexia reaction,” which is almost never seen with Vemurafenib [Zelboraf], has been seen in a substantial percentage of patients taking Dabrafenib [Tafinalar]. “We don’t know yet about the off-target mechanisms of these differences and how much may be due to the vehicle or the formulation for each of these oral agents,” she added.

However, the biggest problem with the BRAF inhibitors in the treatment of melanoma has been the lack of durable response: These drugs “tend to work for an average of 5 to 6 months,” Dr. Margolin noted. What to do when patients fail on these drugs remains a challenge, she added.

Ultimately, combination therapy with a BRAF inhibitor (such as Vemurafenib [Zelboraf]  or Dabrafenib [Tafinalar]) plus a MEK inhibitor (such as Trametinib [Mekinist]) is “likely to be most valuable for improved and lasting results,” according to Dr. Margolin. Firstclinical results along these lines have been published in the New England Journal of Medicine at the end of last year.

FDA Approves Companion Genetic Diagnostic Test for Erlotinib [Tarceva] in NSCLC

May 14, 2013 – The US Food and Drug Administration (FDA) today announced the approval of the cobas EGFR Mutation Test, a companion diagnostic for the cancer drug Erlotinib (Tarceva). This is the first FDA-approved companion diagnostic that can detect epidermal growth factor receptor (EGFR) gene mutations, which are present in approximately 10% of non-small cell lung cancers (NSCLCs).

The approval of this test comes at the same time as an expanded indication for Erlotinib (Tarceva). The FDA has also announced a labeling change for Erlotinib (Tarceva), and the drug is now indicated for first-line use in patients with metastasized NSCLC that tests positive for EGRF mutations. Until now, the official indication was second- or third-line use in advanced NSCLC.

“The approval of the cobas EGFR Mutation Test will allow physicians to identify non-small cell lung cancer patients who are candidates for receiving Erlotinib (Tarceva) as first-line therapy,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, in a statement. “Companion diagnostics play an important role in determining which therapies are the safest and most effective for a particular patient.”

The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data showing progression-free survival in NSCLC patients with specific types of EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) for 10.4 months when they received Erlotinib (Tarceva) treatment, compared with 5.4 months for those who received standard therapy.

In the United States, Erlotinib (Tarceva) is currently the only drug available for use in EGFR-positive NSCLC, although elsewhere in the world, another similar drug is widely used: Gefitinib (Iressa). A third drug in this class of EGFR tyrosine kinase inhibitors (TKIs), Afatinib (Tomtovok, by Boehringer Ingelheim), is close to approval, with an FDA decision expected in July 2013. Afatinib will also have its own companion diagnostic test (Therascreen EGFR PCR Kit, from Qiagen).

Using an EGFR TKI in the first-line treatment of EGFR-mutated NSCLC is recommended by several clinical guidelines, including the American Society of Clinical Oncology.

Patient outcomes are significantly better when compared with chemotherapy, so much so that it “would be a tragedy not to use” an EGFR inhibitor in EGFR-positive patients, according to one expert in the field, Edward Kim, MD, PhD, assistant professor of medicine and director of clinical operations at the University of Texas MD Anderson Cancer Center, in Houston. To not know whether the tumor is mutation-positive is not acceptable anymore, he added.

However, testing for mutations is not yet routine, and there are difficulties with obtaining lung cancer samples of sufficient size and quality, as well as disagreement over which is the best method for obtaining such samples, as recently reported by Medscape Medical News. In addition, there are issues with the costs of such testing, as outlined in a comment from a surgeon is response to that article.

The cobas EGFR Mutation Test is manufactured by the Roche Molecular Systems. Erlotinib is comarketed by California-based Genentech, a member of the Roche Group and OSI Pharmaceuticals.

Could a biomarker rescue Lumiracoxib [Joicela], formerly known as [Prexige]? A genome-wide study identifies a strong assossiation of the HLA allele DQA1*0102 with Lumiracoxib [Joicela]-related serious liver injury

April 23, 2011 – In the history of flawed and/or market-withdrawn drugs, Lumiracoxib [Joicela], formely known as [Prexige], may only be a footnote, hardly comparable to the attention received by the high flying but ill-fated Rofecoxib [Vioxx], Troglitazone [Rezulin], and more recently Rosiglitazone [Avandia].

However, Lumiracoxib [Prexige] may make a mark after all in the history of pharma beyond its missed revenue opportunity or beneficial impact on patients. The drug is a selective COX-2 inhibitor, indicated for symptomatic relief of pain from osteoarthritis. COX-2s inhibitors, such as the infamous Rofecoxib [Vioxx], seem all but off the market in the US because of their cardiovascular side effects. Lumiracoxib [Prexige] seems to bind to a different site on the COX-2 receptor, which may give it advantages that lift it from under the Rofecoxib [Vioxx] shadow: minimal cardiovascular side effects, high selectivity, rapid clearing from the circulation and absorption into the inflamed joint.

Lumiracoxib [Prexige] received European marketing authorization in November 2006 and was launched in parts of Europe the following year. Because of its own safety shortcomings such as rare but potentially fatal liver injury at higher doses, from 2007 onwards, Lumiracoxib [Prexige] was withdrawn from most European markets, as well as from the Australian and Canadian markets. Lumiracoxib was never approved by the American Food and Drug Administration (FDA), mostly for safety reasons.

Could the biomarker DQA1*0102 rescue Lumiracoxib?

In a recent study by Singer et al., published in 2010 in Nature Genetics 42, pages 711-714, a case-control genome-wide association study was performed on 41 Lumiracoxib-treated patients with liver injury (cases) and 176 matched Lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 x10 to -10). These findings were replicated in an independent set of 98 Lumiracoxib-treated cases and 405 matched Lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 x 10 to -12). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501 -HLA-DQB1*0602 -HLA-DRB5*0101 -HLA-DQA1*0102, most significant allele P = 6.8 x 10 to -25, allelic Odds ratio = 5.0, 95% CI 3.6 – 7.0).

In princip, these results offer the potential to improve the safety profile of Lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from Lumiracoxib treatment. In fact, Novartis Pharma, the makers of Lumiracoxib, applied with the European Medicines Agency (EMEA) for a centralized marketing authorisation for Lumiracoxib [Joicela], in December 2009. According to this application, Lumiracoxib [Joicela] was intended, in a 100 mg film-coated tablet form, to be used for symptomatic relief in the treatment of osteoarthritis of the knee and hip in patients who are non-carriers of the DQA1*0102 allele. In essence, patients who test negative for the DQA1*0102 allele are expected to have a low risk for the development of serious liver side effects and could therefore safely take the drug. Those patients who test positive for the DQA1*0102 allele, however, should not get the drug.

This approach would constitute the first example throughout the pharmaceutical industry where a biomarker strategy rescued a drug, previously withdrawn from the markets because serious adverse effects (i.e., liver injury).  For the pharmaceutical industry, such a strategy for rescuing drugs previously flawed by serious drug adverse effects may hold tremendous appeal (cases such as Exanta, Galvus, etc., come to mind), even if the ultimate market for such rescued drugs may be nowhere near the original projections.

Lumiracoxib [Joicela] and its companion test: Not quite there yet

As we learned by mid-April 2011 from an announcement by the European Medicines Agency (EMEA), the application of the marketing authorisation for Lumiracoxib [Joicela] was withdrawn by Novartis. At the time of the withdrawal it was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP).

In its official letter, the company stated that its decision to withdraw the application was based on its inability to address the CHMPs request to provide additional data within the time frame allowed in the centralised registation procedure. We should take note here that withdrawal of an application does not prejudice the possibility for the company to make a new application at a later stage. In any case, more information about Lumiracoxib [Joicela] and the state of the scientific assessment at the time of withdrawal will be made available in a question-and-answer document. This document, together with the withdrawal letter from the company, will be published on the Agency’s website after the next CHMP meeting on 16 to19 May 2011.

Regulatory Science Update: FDA and International Serious Adverse Events Consortium (SAEC) Complete Third Data Release

February 21, 2010 – In the field of pharmaco- and toxicogenetics of serious adverse drug reactions (sADRs) in humans, we learn today from a press release by the US Food and Drug Administration (FDA) of the completion and release by the FDA and the International Serious Adverse Events Consortium (SAEC) of the third data set with  focus on the genetic basis of drug-induced liver injury (DILI) and serious skin reactions (SSRs).

The data focus on the genetics associated with DILI and SSR and may help researchers to better predict an individual’s risk of developing these serious complications.

Drug induced liver injury occurs in a small subset of patients and is often associated with a drug that is an unpredictable liver toxin, and may be the cause of acute liver failure in some patients. Although the exact mechanism behind drug-induced liver injury is unknown, research suggests that a person’s genes contribute to their likelihood of developing this injury.

Drug-induced SSRs, such as Stevens-Johnson, present as allergic-like skin reactions (blistering and peeling of the skin) and are considered serious enough to discontinue treatment with the medication. These reactions can be fatal if the signs and symptoms are not quickly recognized.

The released research data relating to drug-induced liver injury (368 cases) and serious skin reactions (15 cases), complement the already released data from the SAEC’s December, 2008 and May, 2009 data releases.

“FDA is pleased with the Consortium’s progress,” said ShaAvhree Buckman, M.D., Ph.D., director of the Office of Translational Sciences in the FDA’s Center for Drug Evaluation and Research. “The continued accumulation of scientific information on the genetic basis of adverse drug events provides researchers with invaluable tools for understanding why some people respond to medicines differently than others.”

The SAEC is a nonprofit partnership of 10 international pharmaceutical companies, the Wellcome Trust, and academic institutions focused on research relating to the genetics of drug-induced serious adverse events.

Researchers who enter into a data use agreement can obtain free access to the data to generate custom data inquiries and obtain immediate results on the genetic basis of adverse drug events.

For more information on the International Serious Adverse Event Consortium (SAEC), go to http://www.saeconsortium.org

Information on previous SAEC data releases, follow the links below:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm109077.htm, or
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm163067.htm

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Inherited risk factors increase odds of developing childhood acute lymphoblastic leukemia (ALL)

January 16, 2010 – This contribution has just been published in the ScienceBlog – Pharmacogenetics at this locoation. It is presented here in its original state and with all credentials and rights resting with the original author.

Scientists at St. Jude Children’s Research Hospital have identified inherited variations in two genes that account for 37 percent of childhood acute lymphoblastic leukemia (ALL), including a gene that may help predict drug response.

The findings stem from the first complete search of the human genetic blueprint or genome to look for inherited risk factors for ALL, the most common childhood cancer. Published in the August 16 advance online issue of Nature Genetics, the work offers the first proof based on a complete survey of the human genome that inheritance plays a role in childhood ALL.

Mary Relling, Pharm.D., St. Jude Pharmaceutical Sciences chair and the paper’s senior author, estimated that individuals who inherited variations in genes known as ARID5B or IKZF1 are almost twice as likely to develop ALL as those without the variations. Even then, she said, the risk remains low. ALL strikes roughly one in every 75,000 Americans. Sixty percent are children and teenagers.

“The genetic variations alone are not enough to cause the cancer. Like all cancers, pediatric ALL is a multi-factor disease,” Relling explained. “But these findings may give us a handle on the mechanism of the disease and drug responsiveness to it.”

Exactly the same genes, ARID5B and IKZF1, were confirmed to be altered in British children with ALL. That study was published by the Institute of Cancer Research in Surrey, England, in the same issue of Nature Genetics.

In the St. Jude study, researchers collaborated with colleagues from the Children’s Oncology Group (COG), who provided additional cases for genetic analysis. COG is an international group of medical institutions that cooperate in research studies and clinical trials of childhood cancer treatment.

Researchers scanned the genomes of 441 children with ALL and a control group of 17,958 cancer-free individuals for more than 300,000 common genetic variations known as single nucleotide polymorphisms or SNPs.

The search found 18 SNPs that differed significantly in frequency between individuals with and without ALL. Six of the 18 SNPs were associated with one of the four main subtypes of ALL.

The six included two SNPs linked to the ARID5B gene. About 11 percent of those in the control group inherit the leukemia-risk ARID5B variations from both mother and father, Relling said. In comparison, the same high-risk ARID5B SNPs were found in 38 percent of patients with a type of ALL known as hyperdiploid ALL. That subtype accounts for about 20 percent of ALL patients.

Three more SNPs were traced to the genes IKZF1 and DDC, which are next to each other on chromosome 7. IKZF1 is also known as IKAROS. Earlier research from St. Jude and COG linked acquired changes in IKZF1 to an increased risk of ALL relapse. The new evidence tying inherited variation in IKZF1 to an increased risk of developing ALL underscores the need for medications targeting variations in this gene, Relling said.

Both ARID5B and IKZF1 play important roles in normal development of lymphoid or white blood cells, she said. ARID5B belongs to a family of genes that make transcription factors, which help regulate gene activity. “If they have an inherited variation that affects the function of those genes, these are plausible pathways for how a normal lymphoid cell could be disrupted and transformed into a cancer cell,” Relling said.

Inherited variations in ARID5B might also influence patient response to chemotherapy, particularly to the drug methotrexate. “We found this same inherited variation also affected accumulation of the drug in leukemia cells. It accumulates better. That allows us to use a lower dose and still cure the leukemia,” Relling explained. “These findings may identify a new marker that could be used to help decide on doses of methotrexate in patients with varying ARID5B status.”

Scientists are not sure how the SNPs they identified influence cancer risk. But studies of variation in gene expression associated with the ARID5B gene indicate the inherited variations have a biological function. Researchers must still determine what it is.

Other authors of this paper include Lisa Trevino, Wenjian Yang, Deborah French, Geoffrey Neale, James Downing, Susana Raimondi, Ching-Hon Pui and William Evans, all of St. Jude; Stephen Hunger, University of Colorado, Denver; William Carroll, New York University Medical Center, New York; Meenakshi Devidas, University of Florida, Gainesville; and Cheryl Willman, University of New Mexico, Albuquerque.

This study was supported by the National Cancer Institute, the National Institutes of Health/National Institutes of General Medical Sciences Pharmacogenetics Research Network and ALSAC.

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