[Study of cancers as genetic diseases].
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Alleles↗
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Genetics and cancer: a second look. Introduction.
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Female↗
[The cancerous cell. Genetic abnormalities (oncogenes and anti-oncogenes), growth factors, apoptosis and dissemination factors, prognostic incidence].
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Apoptosis↗
Second Strang International Cancer Conference: genetics and the environment New York, USA, 15-16 November 1996.
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Environmental Exposure↗
The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium.
Disruption of the DNA mismatch repair system, characterized by microsatellite instability (MI), plays an important role in the course of human carcinogenesis by increasing the rate of mutations of genes associated with cancers. However, it is not clear which genes are the target genes for mutation in the course of carcinogenesis. Microsatellites within the coding region of the transforming growth factor beta receptor type II (RII) and insulin-like growth factor II receptor (IGF-IIR) genes were reported to be targets for mutation during the course of carcinogenesis in MI+ tumors. Recently, somatic mutations were found in a poly(G)8 tract in the BCL-2-associated X protein (BAX) gene, one of the essential players in apoptosis, in some MI+ tumors. We examined mutations of BAX in MI+ cancers of various organs and found frameshift mutations at the poly(G)8 tract in 5 of 15 (33%) gastric cancers, 3 of 26 (12%) endometrial cancers, and 9 of 22 (41 %) colorectal cancers. In contrast, no such mutations were found in pancreatic cancer. These results suggest that mutations of BAX play an important role in the course of carcinogenesis in the stomach, colorectum, and endometrium.
Apoptosis↗
Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model.
We employed a genetically defined human cancer model to investigate the contributions of two genes up-regulated in several cancers to phenotypic changes associated with late stages of tumorigenesis. Specifically, tumor cells expressing two structurally unrelated bone-related genes, osteonectin and osteoactivin, acquired a highly invasive phenotype when implanted intracranially in immunocompromised mice. Mimicking a subset of gliomas, tumor cells invaded brain along blood vessels and developed altered vasculature at the brain-tumor interface, suggesting that production of those two proteins by tumor cells may create a complex relationship between invading tumor and vasculature co-opted during tumor invasion. Interestingly, the same tumor cells formed massive spontaneous metastases when implanted subcutaneously. This dramatic alteration in tumor phenotype indicates that cellular microenvironment plays an important role in defining the specific effects of those gene products in tumor behavior. In vitro examination of tumor cells expressing either osteonectin or osteoactivin revealed that there was no impact on cellular growth or death but increased invasiveness and expression of MMP-9 and MMP-3. Specific pharmacologic inhibitors of MMP-2/9 and MMP-3 blocked the increased in vitro invasion associated with osteoactivin expression, but only MMP-3 inhibition altered the invasive in vitro phenotype mediated by osteonectin. Results from this genetically defined model system are supported by similar findings obtained from several established tumor cell lines derived originally from human patients. In sum, these results reveal that the expression of a single bone-related gene can dramatically alter or modify tumor cell behavior and may confer differential growth characteristics in different microenvironments. Genetically defined human cancer models offer useful tools in functional genomics to define the roles of specific genes in late stages of carcinogenesis.
Animals↗
[Genetic predisposition to cancer: familial forms of medullary thyroid cancer and breast cancer].
Most cancers appear to be sporadic. However, 5 to 10% of cancers occur in genetically predisposed individuals. This inherited genetic risk is observed in syndromes such as familial polyendocrinopathies or phacomatosis such as neurofibromatosis, but also in familial aggregations of frequent cancers such as breast or colon cancers. Thanks to studies on molecular genetics, it has been possible over the last ten years to localize and to identify a large number of predisposing genes. These discoveries have permitted to better understand the biological basis of the predisposition and to offer counselling by identifying at-risk individuals in those families. In the case of multiple endocrine neoplasia type 2 associated with an elevated risk for medullary thyroid cancer, the gene involved is a protooncogene named RET and located on chromosome 10. Point mutations affecting specific regions of this gene are the basis of the genetic predisposition. For familial breast cancer, a susceptibility gene named BRCA1 has been located on the long arm of chromosome 17. Mutation of this gene (yet to be identified) led to very elevated risk of breast cancer and also in some families of ovarian cancer.
Breast Neoplasms↗
BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian.
OBJECTIVE: Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers, so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways seem largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects. DATA SOURCES, DATA EXTRACTION, DATA SYNTHESIS: The author collected data published in > 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data were extracted and used directly as published whenever possible with a minimum of statistical manipulation. CONCLUSIONS: Although mutations target breast and ovary, a broader spectrum of cancers also occur with statistically significant elevated frequencies. Risks for "all cancers except breast or ovary" are elevated, with some population subgroups differing with regard to how frequently elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate, and colon. The increased risk ranged from about 20% to 60%, with the greatest increases in risk in stomach and pancreas. The collected data show BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful targets for chemotherapy or chemoprevention.
BRCA1 Protein↗
Determinants of preferences for genetic counselling in Jewish women.
INTRODUCTION: Patient preferences are central to the economic appraisal of health services. Cancer genetic services are relatively new, and little is known about clients' preferences. We sought to determine clients' preferences for genetic service delivery, and to identify factors that predict those preferences. METHODS: We studied female participants in the Australian Jewish Breast Cancer Study who were offered a test for ancestral mutations in the BRCA1 and BRCA2 genes. Questionnaires, asking respondents to rank their preferences for functions, or attributes, of genetic counselling were received from 256 women (76% response rate). RESULTS: Sixty-two per cent of the respondents gave their highest preference for information on cancer and genetic risk; 19% gave it to breast and ovarian cancer surveillance; 14% gave it to preparation for testing; and, 5% gave it to direction with decision making. Most ranked direction as their least preferred attribute (53%). Women with a strong cancer family history were less likely to give highest preference to information (52%) and more likely to give highest preference to preparation for testing (22%) (P=0.04; 0.01, respectively). Women with a university degree were less likely to give highest preference to surveillance (15%) (P=0.04). CONCLUSION: Most women offered testing had highest preference for information and lowest preference for direction. We have identified factors that predict highest preference for information, preparation, and surveillance attributes. Understanding preferences and their predictors may assist cancer genetic services to provide clients with greater benefits from counselling.
Adult↗
A genetic approach to cancer epigenetics.
In over 20 years since the discovery of altered methylation in cancer, many epigenetic alterations have been found in human cancer, including global and specific gene hypomethylation, hypermethylation, altered chromatin marks, and loss of genomic imprinting. Cancer epigenetics has been limited by questions of cause and effect, since epigenetic changes can arise secondary to the cancer process and its associated widespread changes in gene expression. Furthermore, mutations in the DNA methylation machinery have not been observed in tumors, whereas they have been for chromatin modification. To address the issue of human cancer etiology, we have taken a genetic approach to cancer epigenetics. One line of investigation has been on the disorder Beckwith-Wiedemann syndrome (BWS). We have found that loss of imprinting (LOI) of the autocrine growth factor gene IGF2 and of the untranslated antisense RNA LIT1, within the K(V)LQT1 gene, account for most cases of BWS, and that cancer risk is specifically associated with LOI of IGF2. Wilms' tumors, both in BWS and in the general population, involve LOI leading to an expansion of nephrogenic precursor cells. We have also developed an animal model for the role of LOI of IGF2 in cancer, showing that it cooperates with Apc mutations to increase cancer frequency, consistent with human data suggesting a severalfold increased cancer risk for this common epigenetic variant in the adult population. These data suggest that a major component of cancer risk involves epigenetic changes in normal cells that increase the probability of cancer after genetic mutation. They suggest a model of cancer prevention that involves the epigenetic analysis of normal cells for risk stratification and cancer prevention strategies.
Animals↗
Molecular genetics of sporadic and familial breast cancer.
Molecular genetic analysis of breast cancers indicates that the mechanisms underlying tumorigenesis are complicated. Many oncogenes and tumour suppressor genes have been implicated, encoding proteins that are important at many levels of cell regulation, from cell surface molecules responding to external signals (eg ERBB2) to nuclear factors controlling gene transcription (eg TP53, MYC). Several correlations have been found between certain genetic events and clinical outcome and have therefore proved useful prognostic indicators. The mapping and cloning of genes important in familial breast cancers (eg BRCA1) have provided the essential tools for pinpointing the genes that may be critical in early stage breast cancer as well as for developing genetic tests for predicting carrier status in breast cancer families. Clarification of the molecular consequences of mutation in breast cancer associated genes is beginning to address the factors that drive a normal breast cell to change into a breast cancer cell. However, these studies are still in their infancy, and considerable research will be required to complete the picture.
Ataxia Telangiectasia↗
Molecular genetics of prostate cancer.
A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns. Up to now among the most consistent changes are those of allelic loss events, with the majority of tumours examined showing loss of alleles from at least one chromosomal arm. Chromosomes 8 and 13 appear to be the most frequently affected, with the former showing both loss of alleles from the short arm and gain of sequences on the long arm. Deletions of one copy of the RB gene are common, whereas deletion and/or point mutation of the TP53 gene is a less frequent event, at least in clinically localized tumours. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in over one third of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. In addition, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting an important role for methylation modulated gene expression in prostate carcinogenesis. Finally, the existence of prostate cancer susceptibility genes is suggested by study of familial clustering of prostate cancer, and it is expected that the identification of these genes will provide insight into critical rate limiting steps in the carcinogenic pathway of both inherited and sporadic disease.
Apoptosis↗
Complementary medicine use among women enrolled in a genetic testing program.
The purpose of this study is to explore complementary and alternative medicine (CAM) use and factors influencing CAM use by women enrolled in a genetic testing program for predisposition to breast/ovarian cancer. A cohort of 236 high-risk women completed baseline questionnaires at enrollment into BRCA1/2 testing program. CAM use and correlates of use were assessed using logistic regression models. CAM was used by 53% of the overall cohort. Cancer survivors reported significantly more use of complementary treatments than did unaffected women (61 versus 42%; P < 0.05). Participants had good overall health behaviors; daily fruit/vegetable consumption was significantly related to CAM use. Increased depression level, knowledge of cancer genetics, and frequency of breast self-examination were significantly associated with using CAM for cancer survivors. Among unaffected women only, cancer risk perception and sunscreen use were significantly correlated with CAM use. Recognition of heightened breast cancer risk is correlated with increased complementary therapy use by unaffected women undergoing genetic testing for cancer predisposition but not to the extent that cancer survivors use these strategies. Any potential effects of the genetic information itself on CAM use, and any possible relationship of CAM use to other risk reduction behaviors, require further research.
Adolescent↗
[Clinical genetics for hereditary cancers: from the viewpoint of physicians working at a hospital specialized in cancer].
In our daily practice, we provide clinical genetic consultation for patients at risk for hereditary cancers. The clinical characteristics of hereditary cancer syndromes in adults differ from those of hereditary diseases in children, although both involve genetic disease. One major difference is the difficulty in diagnosing hereditary cancers. Genetic testing has enabled us to diagnose HNPCC and familial breast and ovarian cancers. Another difference is the possibility to improve the outcomes of hereditary cancer syndromes by medical intervention. Intentional surveillance thus plays a key role in the management of hereditary cancer syndromes. These features make genetic counseling essential for hereditary cancer syndromes, including genetic testing and lifelong disease management. Networking among genetic disease specialists is particularly necessary. Clinical geneticists should be responsible for not only genetic disease but also for genomic information about cancer, with the ultimate goal of providing "order-made" medical consultation and services. Another important goal is the establishment of systems for the comprehensive care of patients and for the career development of specialists to provide regional-based care for persons who have or are at risk for hereditary cancers, including future generations.
Adult↗
[Genetic counseling and clinical genetics services for cancer prone kindreds].
Gene testing elucidates the identification of heterozygous carrier for hereditary cancer and the needs for genetics services are increasing in cancer hospitals. Genetic services include educational explanation for the disease and Mendelian inheritance, risk assessment, orientation for gene testing, post-test counseling for cancer prevention and psychosocial issues, and support services. This review outlines how they are performed in the clinic of cancer hospital.
Female↗
Inherited susceptibility to breast and ovarian cancer.
Approximately 5-10% of breast and ovarian cancer cases are due to an inherited susceptibility. The majority of inherited breast and ovarian cancer susceptibility is due to mutations in the BRCA1 and BRCA2 genes; however, other genes responsible for inherited susceptibility to these diseases are yet to be identified. A small proportion of inherited breast and ovarian cancers are due to other genetic cancer susceptibility syndromes including Li-Fraumeni syndrome, Cowden disease and hereditary non-polyposis colorectal cancer. It is recommended that individuals at risk for inherited susceptibility to breast and/or ovarian cancer who are requesting DNA testing be provided with pre-test genetic counseling and education and post-test counseling and follow-up to ensure that all aspects of genetic testing have been disclosed and that the patient has truly given informed consent.
BRCA2 Protein↗
The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what's genetics got to do with it?
Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer - especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.
Antineoplastic Agents↗
[Hereditary neoplastic diseases (genetic predisposition and cancer syndromes)].
After one decade of molecular genetic studies, little doubt remains that cancer is a genetic disease. While mutations in somatic cells may cause cancer, they don't carry forward to the next generation. In fact, most cancers arise in this way. In some individuals mutations in cancer related genes may be present at the constitutional level, inherited from one of the parents. An individual who carries a mutant allele of an inherited cancer gene has a variable risk of cancer that is influenced by other genetic and non-genetic factors (such as other cellular genes, dietary, lifestyle, and environmental factors). Collectively, the syndromes affect about 1% of cancer patients. During the past decade about 25 different cancer susceptibility genes have been reported to be linked to the known hereditary cancer syndromes. Over the period of the last three to five years, studies of the specific mutations responsible for these syndromes and the cellular signaling pathways disrupted by the mutant proteins have begun to provide unprecedented insights into the molecular origin and pathogenesis of inherited and sporadic forms of cancer. This article reviews the cancer susceptibility genes and cancer syndromes, particularly those associated with common malignancies (breast, prostate and colorectal carcinomas). Results of the mutation analysis in BRCA1 and BRCA2 genes of Hungarian breast/ovarian cancer families will be briefly discussed. These data indicate a strong founder effect for some mutations of BRCA1 gene in Hungary. As a results of recent publicity of discoveries of molecular genetics--particularly those related to common malignancies--due to publicity in the scientific and the lay press awareness and demand for predictive DNA tests have dramatically increased worldwide over the past 3 years. The author, as a member of the Breast Cancer Linkage Consortium, shares the consensus view that genetic testing and genetic counseling for cancer risk together with surveillance and management should for the present be offered only through specialist clinical genetic departments as part of a research evaluation.
DNA, Neoplasm↗