Cancer-causing mutations yield their secrets
16/02/12 07:30 Filed in: Nature
Submitted by S. Pelech - Kinexus on Thu, 02/16/2012 - 07:30.
The latest Nature papers strongly support the concept that aberrant R'-2-hydroxyglutarate (R-2HG) production might contribute to the development of glioblastomas and other cancers and offer some mechanistic insights. It is inferred in these publications and elsewhere that the transforming mutations of isocitrate dehydrogenases (IDH) 1 and 2 result in the loss of synthesis of 2-oxoglutarate (2-OG or alpha-ketoglutarate) from isocitrate and NADP. However, there is also a gain in function whereby 2-OG can be converted to R-2HG by mutated IDH1 and IDH2. Presumably, only one of the IDH genes is mutated in these cancers so that the other isoform is still able to produce 2-OG as a substrate for the mutated IDH isoform to generate R-2HG.
What is particularly remarkable is that in about 11% of nearly 28,000 human cancers tested (highest frequencies in glioblastomas, leukemias and thyroid cancers), IDH1 is almost exclusively mutated at amino acid 132, which is an arginine residue located in the substrate binding site in the wild-type gene. Conversion of Arg-132 to histidine or cysteine in IDH1 account for 83% of the observed mutations in this gene (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=IDH1). This rate of point mutations for IDH1, with such precise location and restricted substitutions is sixth highest that I have been able to find for any human gene linked with cancer.
In IDH2, the equivalent amino acid residue Arg-172 is mutated to lysine in about 1% of over 18,000 human cancers examined. However, Arg-140 in IDH2, also involved in substrate binding, is more commonly altered to a glutamine in nearly 3% of diverse human cancers (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=IDH2).
The loss of function of IDH1 and IDH2 for production of 2-OG from citrate in more than 12% of human cancers may be one of the contributing factors to the Warburg Effect. Cancer cells commonly demonstrate higher rates of glycolysis and anaerobic production of ATP from glucose. The higher requirement for glucose in cancer cells may arise from reduced aerobic synthesis of ATP via the tricarboxylic acid (TCA) cycle, in which IDH1 and IDH2 play key catalytic roles.
It is possible that reduction of carbohydrates in the diet of cancer patients that have the mutations described above in IDH1 or IDH2 might be especially effective in their treatment as their cells would be especially addicted to sugars for survival.
Link to the original blog post.
The latest Nature papers strongly support the concept that aberrant R'-2-hydroxyglutarate (R-2HG) production might contribute to the development of glioblastomas and other cancers and offer some mechanistic insights. It is inferred in these publications and elsewhere that the transforming mutations of isocitrate dehydrogenases (IDH) 1 and 2 result in the loss of synthesis of 2-oxoglutarate (2-OG or alpha-ketoglutarate) from isocitrate and NADP. However, there is also a gain in function whereby 2-OG can be converted to R-2HG by mutated IDH1 and IDH2. Presumably, only one of the IDH genes is mutated in these cancers so that the other isoform is still able to produce 2-OG as a substrate for the mutated IDH isoform to generate R-2HG.
What is particularly remarkable is that in about 11% of nearly 28,000 human cancers tested (highest frequencies in glioblastomas, leukemias and thyroid cancers), IDH1 is almost exclusively mutated at amino acid 132, which is an arginine residue located in the substrate binding site in the wild-type gene. Conversion of Arg-132 to histidine or cysteine in IDH1 account for 83% of the observed mutations in this gene (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=IDH1). This rate of point mutations for IDH1, with such precise location and restricted substitutions is sixth highest that I have been able to find for any human gene linked with cancer.
In IDH2, the equivalent amino acid residue Arg-172 is mutated to lysine in about 1% of over 18,000 human cancers examined. However, Arg-140 in IDH2, also involved in substrate binding, is more commonly altered to a glutamine in nearly 3% of diverse human cancers (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=IDH2).
The loss of function of IDH1 and IDH2 for production of 2-OG from citrate in more than 12% of human cancers may be one of the contributing factors to the Warburg Effect. Cancer cells commonly demonstrate higher rates of glycolysis and anaerobic production of ATP from glucose. The higher requirement for glucose in cancer cells may arise from reduced aerobic synthesis of ATP via the tricarboxylic acid (TCA) cycle, in which IDH1 and IDH2 play key catalytic roles.
It is possible that reduction of carbohydrates in the diet of cancer patients that have the mutations described above in IDH1 or IDH2 might be especially effective in their treatment as their cells would be especially addicted to sugars for survival.
Link to the original blog post.