| Japanese Journal of Clinical Oncology | Pages |
Introducing `Cancer Genetics Report' as a New Section in JJCO: Dawn of Post-sequencing Age of Human Genome Project
Teruhiko Yoshida, Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
The `Instructions to authors' of JJCO defines its scope as `original articles and case reports related to clinical research on cancer and allied fields.' So, where does `clinical' research end and `basic' research begin? The boundary between the two fields is increasingly blurred or even meaningless in some instances. This trend has been largely driven by the rapid advances in molecular genetics, which have revolutionized some of the fundamental concepts of carcinogenesis, and by the massive power of biotechnology. In parallel, more attention has been directed to the rational design of clinical protocol studies, and ELSI (ethical, legal and social issues) are now widely recognized as an integral part of pre-clinical as well as clinical medical research. We increasingly hear the key words, `translational research' and `evidence-based medicine', which illustrate this age of medical science and practice. These notions are not new at all, and almost all generations of medical scientists and clinicians have sought to achieve these goals. What is unique today is that we have finally entered a stage where we can seriously consider the `bench-to-bed' and `bed-to-bench' translation in cancer care, when we seek evidence and new strategy for everyday medical practice.
The major and immediate impact comes from genome research. The Human Genome Project aims to decipher the whole set of human genetic codes, which consists of approximately 3 billion (3x109) base pairs (bps). The project was conceived in the United States, Europe and Japan around 1986, and the forerunner of the project, the United States, officially launched the Project in October, 1990. The National Institutes of Health (NIH) and Department of Energy (DOE) set the initial goal for the year 2005, but rapid technological innovation and fierce competition arising from the private sector, which has realized the immense industrial potential of the human genetic information, prompted a re-planning of the project. It is now expected that the human genome sequencing will be completed by the year 2003, and a `working draft' covering 90% of the total human genome will be available next year, 2000 (1). Even the `working draft' itself will have a significant and widespread impact on bioscience and bioindustry. Oncology will be no exception, and in fact, cancer research has been one of the major driving forces of genome science and a major beneficiary as well.
Although the Science Council of Japan issued a recommendation on the promotion of human genome project as early as October, 1989, Japan lacked a systematic approach and centralized effort, which turned out to be crucial to a competitive project of this size, and the final contribution of Japan to the human genome sequencing will be around 10% in terms of the number of base pairs. More recently, however, the Japanese government is boosting its effort in genome research, such as sequencing 30,000 cDNA clones by 2001, in line with the 10-year program for producing a 25-fold expansion in Japan's biotechnology market (2), a part of the so-called `Millennium Project' of Japan.
Importantly, the `mapping and sequencing' phase of the Human Genome Project is just one step in the long way to the final objective of most of us: promotion of health and welfare of human beings based on human genetic information. For instance, the physiological function of most of the 80,000 human genes will still remain unknown even after 2003. In order to understand their functions and regulations, much work must be done, extending over such diverse and interactive disciplines as conventional molecular and cellular biology, bioinformatics, structural biology and genetically manipulated animal models. A potentially important line of research that directly follows from Human Genome Project is the Protein Structure Initiative, sponsored by the National Institute of General Medical Sciences in the United States (3). The goal of this structural genomics project is to deduce at least 10,000 protein structures within the next five years. Fueled by the explosion of the human genome sequence data, the comprehensive catalogue of protein structures and related technologies would exert a tremendous impact on pharmacology, such as in the area of structure-based drug design and discovery.
In addition to a comprehensive elucidation of the functions of the human gene products, the forthcoming `post-sequencing era' of human genome research demands a special type of effort: a large-scale collection of human genome variations and their association with biological phenotypes. Obviously, such information has a huge value. For instance, susceptibility to many common diseases may be explained by an integration of multiple genetic variations or polymorphisms, leading to the identification of high-risk groups. Effects and side-effects of drugs may be predicted based on the polymorphisms of the genes of certain drug-metabolizing enzymes and of the particular drug target molecules. Once the nucleotide sequences of the disease- or phenotype-associated genetic variations are defined, they can be easily loaded onto a `DNA chip' (4), providing quick and easy access for a genetic test in a clinical setting or even in the market outside medical services.
One type of genetic variation among individuals, single nucleotide polymorphism (SNP) (5), has attracted much attention today, because it is the most frequent type of variation, occurring about once in every 300-1000 bps of the human genome. SNPs of known genes may be associated with particular disease- or treatment-related phenotypes, as described above. In addition, the dense distribution of SNPs over the genome is expected to allow efficient linkage disequilibrium mapping to identify genes involved in complex but common diseases such as sporadic cancers, diabetes, hypertension, asthma and schizophrenia (6, 7).
Many scientists in both industries and academia have recognized the enormous potential of SNPs, and the post-sequencing era of human genome research has already commenced as far as SNPs hunting is concerned. In 1998, a Maryland-based US$300 million-plus venture, Celera Genomics, a unit of Perkin-Elmer, began constructing its own SNPs database (8). In April this year, Wellcome Trust in the United Kingdom, and 10 pharmaceutical companies and 5 medical research centers in the United States and Europe launched a US$45 million not-for-profit collaboration, the SNPs Consortium, which has set its goal to the identification of 300,000 SNPs and the mapping of 150,000 SNPs on human chromosomes within 2 years (9). SNPs in coding sequences of the gene (cSNPs) and those in the proximal regulatory regions are of particularly interest, because they are likely to have a direct impact on the protein products (10, 11). Although the patenting issue concerning human gene and cDNA sequences and their variations is still a focus of intense international dialogue, the matter is apparently a concern of national interest: not only the nation's medical bill but also the competitiveness of the bioindustry, a key to the next century.
All these big projects which directly follow the sequencing phase of the Human Genome Project necessitate a national level systematic approach with a defined time table and a few large-scale core facilities for genome analysis and for DNA bank/database construction. A central headquarters should be established to organize and supervise a joint effort of the industrial, academic and government sectors. However, one important element is still missing from this grand scheme: identification and collection of disease-related germline mutations in a particular family. Conceptually, the difference between SNPs and germline mutations is merely quantitative, with respect to incidence (SNPs are usually defined as those occurring in more than 1% of the general population) and to the degree of associated phenotypes (SNPs may be associated with phenotypic variation within `normal' range).
In the field of cancer, cataloguing germline and somatic mutations of the cancer-related genes is a very important task, especially if they are combined with high-quality pedigree information and clinico-pathological and demographic data; it may provide basic information (i) to find a `hot-spot' of mutation, (ii) to identify any racial or population-based differences in the mutation spectrum, (iii) to elucidate the structure-function relationship of the gene product, paving the way for rational drug development, (iv) to understand and predict phenotypic variations including prognosis, sometimes identifying disease subtypes with distinctive clinical features, (v) to evaluate penetrance and expressivity of the disease by facilitating diagnosis of an asymptomatic carrier, (vi) to identify a disease-modifier gene(s) by facilitating linkage analysis, and (vii) to evaluate the significance of missense mutations, which often poses difficulty in genetic diagnosis, when an undescribed missense mutation is found in a case with limited pedigree information.
Unlike the population genetics-type big programs promoted by a central body of national-level genome research, this pedigree-based analysis can be provided only by individual clinicians, who are knowledgeable about the disease and have good access to patients and their families. A number of mutation databases have been established on the Web (e.g. http:// www.uwcm.ac.uk/uwcm/mg/hgmd0.html, http://ariel.ucs. unimelb.edu.au:80/~cotton/mdi.htm) including the major cancer-related genes such as p53, RB and mismatch repair genes. The list of the target genes will expand rapidly as the Human Genome Project and related research progress. However, these databases, although highly useful, lack a sufficient description of clinico-pathological features and the essential pedigree information.
Therefore, partly to complement the population-based centralized human genome research, JJCO has introduced a venue, `Cancer Genetics Report', to accumulate pedigree analysis of cancer-related germline mutations which are useful for the promotion of cancer research and care. The new section will typically report a previously undescribed germline mutation or polymorphism of a gene which is associated with a cancer. A case report with known mutation or polymorphism may be also considered, if the report can be expected to contribute substantially to the advancement and/or accumulation of our knowledge in the field of clinical cancer genetics. To facilitate rapid preparation and processing of this genetic case report, a short-page format with an accelerated peer review process has been chosen.
This issue of JJCO contains the first example of Cancer Genetics Report, where Sugano et al. reports an interesting Japanese pedigree of Li-Fraumeni syndrome (LFS) which presented with a gastric cancer in the proband and a hepatosarcoma in his son. An isolated case of gastric cancer with relatively young age of onset per se is not uncommon in Japan, but the very rare hepatosarcoma in the first-degree relative prompted germline p53 analysis, which led the authors to the correct diagnosis of LFS. The p53 mutation was found at codon 273, replacing arginine with histidine. Codon 273 is known as one of the hot spots of somatic mutation of p53, but this particular type of germline mutation has been reported only in one other case of LFS.
Instructions for the Cancer Genetics Report are found at the end of each report. We hope that this new section of JJCO further encourages translational research in the oncology field and facilitates the proper development of applied genome/genetic research and related technologies, which are on the verge of transforming the daily practice of cancer care in the next century.
References
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Copyright© 1999 Foundation for Promotion of Cancer Research.
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