Scientists find genes to predict chemotherapy outcome
Massachusetts Institute of Technology (MIT) researchers have identified a set of genes whose expression profiles can predict the extent to which an individual‘s cells will be destroyed by the DNA damaging agent used in chemotherapy preparations. Being able to predict sensitivity to chemotherapy from the expression level of a set of genes could have important clinical applications for selection of cancer treatment.
“A cell line from one person would be killed dramatically, while that from another person was resistant to exposure. It wasn‘t known that cell lines from different people could have such dramatic differences in responses” commented lead author Dr Rebecca Fry, on the novel nature of the results.
The authors postulated that different transcription levels of certain genes in the lymphoblastoid cells between individuals could determine an individual‘s response to DNA damaging agents. They found, by computational analysis, 48 genes for which transcription levels could predict susceptibility to the alkylating agent to an astonishing accuracy. Two such genes were MYH and C21ORF56, whose transcripts are translated to proteins that are eminently involved in pathways associated with cancer growth.
The researchers used 24 separate cells lines from healthy volunteers to assess their sensitivity to N-methyl-N-nitro-N-nitrosoguanidine (MNNG), an alkylating, DNA damaging, agent, which produces toxic methylated bases which can trigger apoptosis via the DNA mismatch repair (MMR) pathway. They isolated three groups of genes whose expression levels may indicate MNNG sensitivity. These were, 48 genes identified in basal conditions, 39 genes identified by the ratio of their expression in basal and MNNG treated conditions and 121 genes identified in MNNG treated conditions.
The ability of each of these set of genes to predict MNNG sensitivity was then assessed. The set of genes identified in basal conditions was found to be the most accurate, with 94% accuracy.
One of the genes in the 48 identifed was MGMT, which encodes MGMT DNA repair methyltransferase protein which can repair methylated base pairs and so protect the cell from destruction caused by MNNG. In fact, expression rates of this gene have already been associated with prediction of chemotherapy outcome in glioblastoma. However, this study has found that there are genes in the group of 48 that show a stronger correlation to MNNG sensitivity and so may have more accuracy as predictors. Furthermore, they found that no single gene-expression profile gave a prediction of MNNG sensitivity as accurately as the group of 48 genes together.
The report ends with a call for further research to shed further light on why such differences in response are seen and how these differences will further cancer treatment. The authors concluded that “We propose that upon exposure of these cell lines to other environmental toxicants and cancer chemotherapeutics we will discover more genes of hitherto unknown function responsible for interindividual differences in sensitivity to DNA damaging agents”.
Source: Fry RC, Svensson JP, Valiathan C et al.: Genomic predictors of interindividual differences in response to DNA damaging agents. Genes Dev. 22(19), 2621–2626 (2008).
SNPs Found to be Linked to Asthma in White American Children but not in African–American Children
A study of data from children‘s hospitals across the USA has shown that the relationship between variants of certain genetic markers and the increased risk of asthma observed in children from Germany and Britain is also observed in white American children, but that the association is not seen in African–American children.
The paper, by researchers from the Children‘s Hospital in Philadelphia, PA, USA, highlights the association between SNPs in the ORMDL3 gene on chromosome 17 and the occurrence of asthma in white American children.
Lead researcher of the study, Dr Hakon Hakonarson describes their findings, “We replicated the European findings among [white] American children, and showed that the gene plays a role in asthma of any severity level”.
A total of seven of the nine SNPs analysed in the 3390 white American children studied, including 807 with asthma and 2583 without asthma, were found to be strongly associated with asthma. These findings also confirmed those found in the previous European study. The study‘s participants also involved 3429 African–American children, that included 1456 with asthma and 1973 without asthma, their analysed DNA showed no association between the ORMDL3 SNPs and asthma risk.
The consequences of these discoveries are explained by Dr Hakonarson, “The biological mechanisms by which genetic variants contribute to asthma are not well understood. However, we will continue our investigations, to shed light on how we might use genetic knowledge to develop more effective treatments for this common disease. These treatments will be a form of personalized medicine, better tailored to the genetic makeup of the individual patient”.
Source: Sleiman PM, Annaiah K, Imielinski M et al.: ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. J. Allergy Clin. Immunol. (2008) (Epub ahead of print).
Genomic Analysis May Identify an Individual‘s Risk of Bladder Cancer
Links between two SNPs and the elevated risk of urinary bladder cancer (UBC) in Europeans have been observed in a recent study. Subjects in Iceland, the Netherlands and in seven other studies across eight other European countries took part, totalling 1803 UBC sufferers and 34,336 controls.
Kari Stefansson, CEO of deCODE, explains the potential significance of the results, “In all cancers, the ability to identify individuals at high risk, screening them intensively and intervening early, is the key to improving prevention and outcomes. We expect that the detection of these and other risk variants will soon be employed to complement the assessment of standard risk factors for bladder cancer”.
Approximately 20% of those of European ancestry are estimated to be homozygous for the T allele of rs9642880 on chromosome 8q24. The study conducted by scientists from deCODE genetics of Reykjavik, Iceland in collaboration with researchers at Radboud University Medical Centre in the Netherlands, found that T allele homozygotes were 50% more at risk of UBC onset than those not carrying the T allele. A 40% higher risk of UBC in homozygotes for another genetic variant on chromosome 3 was also observed, though this was shown to have a weaker association.
Chromosome 8q24 has also been linked with breast, colorectal and prostate cancers, though the four SNPs, previously associated with these cancers were not implicated in a higher risk of UBC. However, Dr Stefansson thinks there may be more general links to be discovered, “We are working to identify the common thread of variants we and others have discovered on chromosome 8q24 that confer risk of several forms of cancer, including prostate, breast, colorectal and now bladder. If a common molecular mechanism exists, it could provide an important insight into oncogenesis more broadly”. The study‘s findings are planned to also be integrated into the deCODEme™ personal genome scan.
Source: Kiemeney LA, Thorlacius S, Sulem P et al.: Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet. PMID: 18794855 (2008) (Epub ahead of print).
PTC124: A Drug for Personalized Cystic Fibrosis Treatment
Administration of PTC124 to pateints who have a premature stop codon in the CFTR gene has led to promising results in combating the symptoms of cystic fibrosis.
Researchers at Hadassah Hebrew University Hospital in Jerusalem, Israel, have collected promising data during a prospective Phase II trial with PTC124, a drug developed to combat cystic fibrosis (CF) caused by antisense mutations in the mRNA of the cystic fibrosis transmembrane conductance regulator (CFTR).
Cystic fibrosis describes the condition where an individual does not have or has dysfunctional CFTR protein. CFTR is a membrane protein involved in chloride ion transport. Loss of CFTR function inhibits chloride ion transport across the membranes of the lungs, liver, pancreas and intestines. This leads to thickened, sticky mucus build up, which causes damage to the lungs and intestines and prevents absorption of fat soluble vitamins. Loss-of-function of CFTR can be due to a number of different causes and types of mutations and so it has been difficult to find cure-all therapies. Trials like this one, where a subset of CF sufferers are targeted for treatment may represent the future for successful CF therapy.
The researchers explained that, “This trial exemplifies the concept of personalized medicine: integrating selection of patients with a specific genetic defect, use of a treatment designed to overcome that defect in gene expression, and direct assessment of protein function within disease-affected tissues”.
It is estimated that 10% of CF cases are attributed to inhibition of translation of the CFTR protein by the presence of premature stop codons in the CFTR mRNA, the result of antisense mutations. PTC124 was designed to allow ribosomes to complete translation of the CFTR mRNA by passing over these stop codons. The researchers hope that this drug may be used to successfully treat CF in sufferers with these CFTR mutations.
PTC124 was given to participating subjects for 14 days at a dose of 16 mg/kg followed by a 14 day period without the drug. This cycle was then repeated but with a higher dose of 40 mg/kg. Total chloride ion transport, CFTR-mediated chloride ion transport and response to treatment were measured at the end of each 14 day segment of the trial. An increase in CFTR-mediated chloride ion transport was observed, mean difference of -7.1 mV for the 16mg/kg dose and -3.7 mV for the 40 mg/kg dose and total chloride ion transport was also increased in both cycles.
The results were promising and the authors concluded that, “In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.” Further trials and development are certainly needed, but in future, PTC124 may deliver successful treatment CF in those with antisense mutations in the CFTR gene. However, it seems that CF patients whose condition is the result of other causes will have to wait for a drug targeting those causes to be developed.
Source: Kerem E, Hirawat S, Armoni S et al.: Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective Phase II trial. Lancet 372(9640), 719–727 (2008).