Mapping The Cancer Genome

ONCNG Oncology, January 2010, Volume 11, Issue 0110

For the first time, scientists have constructed a complete genetic map for two types of cancer: small cell lung cancer and malignant melanoma.

For the first time, scientists have constructed a complete genetic map for two types of cancer: small cell lung cancer and malignant melanoma. The melanoma DNA came from a 45-year-old man, and the lung cancer cells were sampled from a 55-year-old man. The research team compared the genetic sequence of the diseased cells with that of healthy cells from the same patients, documenting all genetic mutations. In the lung cancer cells, researchers identified 23,000 mutations, most attributable to chemicals in cigarette smoke known to adhere to and deform DNA. According to the investigators, a typical smoker would acquire one mutation for every 15 cigarettes smoked, or approximately one mutation per pack of cigarettes. The melanoma DNA contained 33,000 mutations, the majority of which arose from ultraviolent exposure via direct sunlight. Both projects were completed by British geneticists from Wellcome Trust Sanger Institute in Cambridge, a member of the International Cancer Genome Consortium (ICGC), and published in Nature.

Professor Mike Stratton, who co-led the research team, said it took a few months to sequence each genome. The team decided to focus on these two cancers because of their established environmental causes. Data suggested that the underlying process of cancer development was underway long before the disease was detectable. “We have been able to explore deep into the past of each tumor, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumor became apparent,” said

Professor Stratton.

The majority of mutations in the two cancers appeared to be passenger mutations, described as inconsequential or harmless. Only two mutations in the lung cancer DNA and three in the melanoma DNA were identified conclusively as driver (or somatic) mutations. “All cancers carry both driver mutations, which are cancer genes and which contribute to cancer development, and passenger mutations, which have essentially just been carried along for the ride. At the moment, it is not known in this or any other cancer how many driving mutations there are,” he said, but added that it would not be far-fetched to speculate that there are 5 to 10 driver mutations in each cancer. Professor Stratton predicted the actual number would become clearer over the next 5 to 10 years, after additional cancer genomes have been sequenced in their entirety.

“Other cancer cases of the same type—in this case, melanoma and lung cancer—will likely have some of the same genes carrying driver mutations but equally will probably have some different cancer genes with driver mutations,” Professor Stratton said. Noting that passenger mutations are randomly distributed, he said “one would expect these to be different in every cancer.”

Another interesting observation from the studies is evidence of the genome’s attempt to “defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation,” said Professor Stratton. “Our cells fight back furiously to repair the damage, but frequently lose that fight.”

Unraveling the Human Genome

When Gregor Mendel, an Augustinian priest and scientist born in the Austrian Empire, performed his experiments with pea plants in the mid- 1800s, scientists could see only the evidence of genes at work but not the genes themselves. It would be nearly a century before British biophysicist and chemist Rosalind Franklin captured the first clear image of genetic material—DNA— using a technique called X-ray diffraction. Franklin’s photograph and preliminary data assisted Francis Harry Compton Crick and James D. Watson in developing an accurate double helix model of the genetic molecule in 1953, for which they later won the Nobel Prize in physics.

Fifty years later, the Human Genome Project, a collaboration of international scientists at universities and research centers, released a nearly complete map of humankind’s genetic makeup. Finished 2 years ahead of schedule, the 13-year project estimated that the human genome contains anywhere from 20,000 to 25,000 genes. Deciphering the genome has transformed the practice of medicine, leading to innumerable medical breakthroughs. In no discipline has this been more evident than oncology, with many recent advances closely trailing discoveries in genetics and molecular biology.

At ASCO’s annual meeting in May 2009, renowned geneticist Burt Vogelstein, MD, director of Ludwig Center at Johns Hopkins, described how he sees the human genome. “I look at the human genome as simply a series of books, an encyclopedia, where each gene is a page containing about 1500 As, Cs, Ds, or Gs, and each book is 1000 pages, which means it contains 1000 genes,” he said. “There are, of course, 46 books—23 from the mother and 23 from the father.” He then explained how cancer fits into the picture. “Of these 40,000 pages, there are only 44 with typographical errors; [there are] 11 missing pages and 8 duplicated pages. That’s really not very much,” he said. “If you were to make an encyclopedia and only had this many typos in it, you’d be pretty satisfied.” This “more than 99.9%” commonality between malignant and normal cells, however, is what makes cancer so much harder to treat than bacterial infections, he said.

Genome Sequencing

Decoding the genomes of various cancer types has become a research priority. In 2008, several of the world’s top geneticists united to establish the International Cancer Genome Consortium (ICGC), with the aim of identifying the genetic roots of 50 major cancer types. The ICGC works to coordinate cancer genome sequencing across the globe, standardizing procedures and facilitating data sharing in the hopes that this will lead to rapid advances in prevention, detection, and treatment.

Historically, complete genome sequencing has been prohibitively expensive outside of the research center. In 2007, Dr Watson’s genome was sequenced for nearly $1 million and presented to him on DVDs. By last year, the cost of genome sequencing had dropped to approximately $100,000 per patient. Then, in November 2009, the startup company Complete Genomics reported in Science that it had whittled the cost down to an all-time low of $5000 per genome. Several companies are now racing to develop a method that will allow the human genome to be sequenced for a relatively modest $1000, which would allow almost anyone to have his or her genome sequenced. Complete Genomics says it hopes to perform complete genome sequences for at least 10,000 patients in 2010.

Professor Stratton said he believes this will soon lead to changes at the practice level in oncology. “Within a decade, we believe that improvements in the technology and reduction in the costs of DNA sequencing will mean that whole cancer genome sequencing to produce comprehensive catalogues of somatic mutations like the ones seen in the two cancers we have just published will become part of the routine diagnostic repertoire of tests for patients with cancer,” he said. The researchers at Sanger also believe that data from their studies and future sequencing of additional tumor types will lead to the development of new targeted therapies, furthering the effort to personalize care for patients with cancer.

Dr Vogelstein shares Professor Stratton’s belief that continued mapping of cancer genomes will open up opportunities for new therapies, particularly in immunotherapy. “In a few years, when cancers become much easier to sequence,” he told the audience at ASCO, “one can determine the sequence of all genes in a cancer...and make a vaccine based on that particular tumor’s mutated gene and its ability to be recognized by the immune system.”

What’s Next for ICGC

The next project for Professor Stratton’s team is mapping 1500 breast tumors, funded by a multimillion-dollar grant from the ICGC. Based on preliminary data from 24 tumors, which Professor Stratton described as “astounding,” he said he believes they will find that breast cancer consists of more tumor categories than previously thought. “The genetic architecture suggests that we’re probably going to be dealing with at least 5 to 10 different animals,” he said.

The ICGC has also funded what it describes as “the largest and most ambitious biomedical research project since the Human Genome Project” by a group of researchers at the German Cancer Research Center and four other cancer institutions in Heidelberg. In early 2010, the centers will begin analyzing 300 tumor samples from various types of pediatric brain tumors and 500 samples from common adult brain tumors in an effort to identify some of the causes of these malignancies.