|Dr. Bert Vogelstein gives recent Trent Lecture.
Researchers have published 852 studies describing the genomes of 23 different cancers over the past half century and a number of things have become clear. Though every cancer is different, tumors tend to have a similar number of gene mutations, Dr. Bert Vogelstein told an audience attending the 10th annual Jeffrey M. Trent Lectureship in Cancer Research. The lecture, held recently in Natcher Conference Center, is sponsored by NHGRI.
“Mutations are just clocks,” said Vogelstein, a cancer genetics pioneer at Johns Hopkins University School of Medicine. “Every time a cell divides it mutates at a low rate and those changes are recorded in the cancer genome.”
Vogelstein is the first researcher to explain the molecular basis of a common human cancer. His studies in this area comprise the most highly cited body of work not only in cancer research, but also in all branches of science. His initial hallmark discovery was a tumor suppressor gene in colorectal cancer, and most other tumor types, called TP53.
His talk was divided into two themes. The first pertained to deciphering cancer genomes and the second explored ways to exploit them. Cancer genomes, like individual genomes, comprise the sequence and structure of a cell’s DNA, but in a cancer cell or tumor. Researchers have generated vast amounts of data about cancer genomes in more than 125 whole genome studies and more than 725 whole exome studies to date. “This has really revealed the details of what the cancer genomes look like and has greatly illuminated the genetic basis as well as the physiologic basis of cancers,” said Vogelstein.
How many mutations occur in the typical cancer cell? “The answer to that question is now clear,” he said. Most cancer tumors have between 20 and 80 mutations. The range includes mutations that affect coding for amino acids. Exceptions to this low-mutation-count rule include tumors that have a DNA repair defect, which would result in a rapid accumulation of mutations per tumor.
From that straightforward enumeration, Vogelstein drew his audience into the intricate world of mutation analysis. He explained that cancer tumors result from the combined effect of gene mutations over long periods.
Scientists now know that the mutation rate in cancer genomes—at the DNA base-pair level—is only marginally higher than for normal cells. But cancers can have other kinds of alterations in their genome that cause structural changes in tumors, particularly deletions of tumor suppressor genes, amplifications of cancer-promoting oncogenes and translocations of either of those genes. Additionally, environmental exposures to carcinogens can cause higher mutation levels, as in the lung cancer of smokers and melanoma from excessive sun exposure.
Current researchers are challenged to conduct genomics and epigenetic studies that further characterize cancer. Epigenetics considers the inherited changes in the genome caused by factors other than DNA sequence changes. Heightening the challenge is the fact that any two cancer tumors are not the same. Vogelstein said that this heterogeneity of tumors lends added importance to the area of personalized medicine.
The second half of his talk focused on exploiting cancer genomes for human health. He outlined three aspects of realizing the benefit of this science — patient management, therapeutics and cancer prevention.
He concluded with an early detection plan involving cancer genomics. The heart of the plan is an annual medical office visit and collection of blood and other tissue samples. A doctor would order standard cancer biomarker analysis along with DNA sequence screening for genetic alterations of the samples. Sophisticated imaging also is part of the detection plan. “The trick will be to design these tests in a cost-effective, high-throughput manner,” Vogelstein said.