A news item appeared this week saying that British researchers have succeeded in creating complete genome mappings for normal tissues, lung-cancer tissues and melanoma tissues in a single patient. While the result is an exciting breakthrough in one sense, it also highlights the very long way there is still to go in decoding cancer genomes and using this information practically to identify cancer susceptibilities, to identify cancer preventative measures and to identify new anti-cancer therapies. I will say a few words about the background of this work, describe the new finding and mention a practical use of existing knowledge of cancer-related gene polymorphisms.
The website of the The Cancer Genome Project of the Wellcome Trust Sanger Institute in the UK provides an introduction: “All cancers occur due to abnormalities in DNA sequence. Throughout life, the genome within cells of the human body is exposed to mutagens and suffers mistakes in replication. These corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilised egg. Occasionally, one of these somatic mutations alters the function of a critical gene, providing growth advantage to the cell in which it has occurred and resulting in the emergence of an expanded clone derived from this cell. Acquisition of additional mutations, and consequent waves of clonal expansion result in the evolution of the mutinous cells that invade surrounding tissues and metastasise. One in three people in the Western world develop cancer and one in five die of the disease. Cancer is therefore the commonest genetic disease. — The identification of genes that are mutated and hence drive oncogenesis has been a central aim of cancer research since the advent of recombinant DNA technology. The Cancer Genome Project is using the human genome sequence and high throughput mutation detection techniques to identify somatically acquired sequence variants/mutations and hence identify genes critical in the development of human cancers. — –“. “The census is not static but rather is updated regularly/as needed. — Currently, more than 1% of all human genes are implicated via mutation in cancer. Of these, approximately 90% have somatic mutations in cancer, 20% bear germline mutations that predispose to cancer and 10% show both somatic and germline mutations.”
The site classifies known cancer genes as follows by type of genetic error:
|Sorted By Number|
Clicking on any of the error categories will show the oncogenes in the category.
A discussion of genetic errors can be found in my blog entry Gene variations and diseases – far from simple.
The new findings
The 16 December advance online publication by members of the Wellcome Trust Sanger Institute is entitled A comprehensive catalogue of somatic mutations from a human cancer genome. By sequencing the entire genome of one patient with lung cancer and melanoma three times: once in healthy cells, once in lung cancer cells and once in melanoma cells, it was possible to identify the mutated genes associated with each of the two types of cancer. Amazing numbers of mutations were found: 33,000 in the melanoma genome, 23,000 in the lung cancer genome.
A fascinating aspect of this work is discovery of traces of pre-disease history in the mutated genes including the efforts of the body’s genetic repair mechanisms. “These are the two main cancers in the developed world for which we know the primary exposure,” explains Professor Mike Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute. “For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight. With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent. — “We can also see the desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation. Our cells fight back furiously to repair the damage, but frequently lose that fight(ref).”
A companion December 16 advance online publication A small-cell lung cancer genome with complex signatures of tobacco exposure relates to the mutational process leading from tobacco smoking to lung cancer and how the footprints of this process can be found in the mutated genes found in the cancer cells. “Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident.” Lung cancer kills about 1.3 million people a year worldwide.“
“In the melanoma sample, we can see sunlight’s signature writ large in the genome,” says Dr Andy Futreal, from the Wellcome Trust Sanger Institute. “However, with both samples, because we have produced essentially complete catalogues, we can see other, more mysterious processes acting on the DNA. Indeed, somewhere amongst the mutations we have found lurk those that drive the cells to become cancerous. Tracking them down will be our major challenge for the next few years(ref).”
The work leaves many questions still to be answered such as: One is “Which gene mutations are primary and essential to the cancer and which ones are just going along for the ride?” Which gene mutations lead to which others, how, when and why?” Expanding the research to include more people with the same cancers and people with other cancers may help to answer the questions. There are perhaps 100 other kinds of cancer that can be studied in the same way, so there is a long ways yet to go.
Benefits of genomic profiling of cancers could be enormous in the realm of personalized medicine, such as:
· identification of cancer susceptibilities long before occurrence of actual cancers,
· being able to know how far along a cancer-susceptible person is from actually manifesting the disease,
· knowing how to stop disease progression at that point,
· new lifestyle, drug, genetic and epigenetic interventions to prevent occurrence of and cure of specific cancers.
There is already some payoff being realized from knowledge of certain specific gene mutations, for example the BRCA1 and BRCA 2 mutations. These mutations are both known to be associated with increased risk for breast and ovarian cancers. The December 17, 2009 report “Breast cancer patients with a particular gene mutation are diagnosed years earlier than the previous generation who also had the disease, according to a study conducted at The University of Texas M.D. Anderson Cancer Center. — Background information provided in the study’s paper revealed that it is estimated that 5% to 10% of all breast cancers are associated with either the BRCA1 or 2 mutation, both of which are associated with an increased risk for breast and ovarian cancers. Furthermore, according to the American Cancer Society (ACS), women with BRCA1 or 2 have a 60% lifetime risk of developing breast cancer, compared to a 12% risk for women in the general population.”