Identical Twins, Different Cancers June 2005 The twin brothers were identical in every way, except for the leukemia they developed—scientists found that they shared some cancer mutations, but not others. This unique opportunity has helped researchers create one of the first timelines describing the way leukemia mutations develop in what started off as identical genomes. These twins were both diagnosed with acute lymphoblastic leukemia (ALL) about the time of their fifth birthday. ALL is the most common form of pediatric cancers and arises through a multi-step process, which takes place as cells accumulate genetic mutations. By knowing which mutations occur first, researchers can better determine the stage of cancer progression. The problem; however, has been finding a way to do the genetic comparisons as the cancer progresses and new mutations are developed. Studying identical twins is a good opportunity to use the same starting point for genetic comparisons. As reported in the October 2004 issue of Leukemia, Dr. Felix Niggli and his colleagues at the University Children's Hospital, Zurich set out to build this cancer timeline by analyzing the twin brothers' neonatal blood and looking for genetic differences. They found that the twins shared an abnormal fusion gene, but that one brother had then developed an independent mutation in a second gene called TEL, while the other did not. These results helped the team construct a multistep model to cancer. The first causative mutation likely happened early during embryonic development, but once divided into separate embryos, each twin developed independently and so did their cancers. To further characterize the different subtypes of cancer each twin developed, the research team compared their gene expression profiles to 31 other cases of pediatric ALL and found that both twins had the ALL subtype, TEL-AML1. Even though both twins were classified into the same subtype, their expression profiles more closely matched the cancer profiles of other children than of each other. Niggli and his team used the GeneChip® Human Genome U133A microarray to simultaneously measure over 18,000 transcripts from each twin, and to then construct patterns of gene expression that could be compared to other cases of pediatric ALL. Using Affymetrix probe sets and software analysis, the scientists were able to identify molecular markers, which were used to characterize and classify the brothers' leukemias. By performing these comparisons, researchers can now predict subclasses of pediatric cancers, which often provide information predictive of clinical outcome or treatment success. The nameless twin brothers in this study have helped researchers develop a much needed timeline describing the way mutations are accumulated in acute lymphoblastic leukemia progression. And by constructing this step by step guide to the way ALL develops, Niggli's team hopes to identify genes that can be targeted for more effective treatment and screened for earlier detection. The author, Thomas Broudy, received his Ph.D. in Microbiology at The Rockefeller University. He then continued his research in this field, first as a postdoctoral associate at The Rockefeller University and later as a postdoctoral scholar at Stanford University.