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PubMed1999

Costs, benefits and limitations of genetic testing for cancer risk.

There has been considerable progress in the identification of predisposing genes involved in many of the rare familial cancer syndromes and in a proportion of the common cancers. Genetic testing for cancer risk is now part of good medical practice in a number of cases, allowing specific cancer screening and prevention to be targeted to those with the greatest need. In some situations, the advantages of testing are less obvious, and careful evaluation of the costs and benefits of testing, and the efficacy of any subsequent intervention, is essential. In the meantime, it is clear that structures must be set up to evaluate demand for testing and deal with it; to inform and educate the public and doctors so that demand is based on understanding of what genetic tests can do; to provide action on test results and to advise and support individuals before and after testing.

Cost-Benefit Analysis↗

PubMed1992

Population genetics of colonic cancer.

BACKGROUND: There are several well known but rare syndromes of inherited colonic cancer. Genetic epidemiologic studies also have demonstrated that relatives of individuals with colonic cancer in general exhibit an excess risk for this malignancy. METHODS: This report reviews the literature pertinent to genetic and familial risk for colonic cancer with emphasis on the recent work that suggests that inherited susceptibility to colonic neoplasms is common. RESULTS: The adenomatous polyposis syndromes are rare inherited colonic cancer conditions caused by a mutant gene which recently has been characterized. Hereditary nonpolyposis colorectal cancer is likewise inherited and may account for up to 5% of cases. The molecular genetics of this disease remain to be clarified. The majority of colonic cancer cases are considered sporadic but are known to often cluster in families. Recent work suggests that inherited susceptibility may be the basis of this familial occurrence. Screening strategies based on inherited and familial risk are suggested. CONCLUSIONS: Knowledge of the familial and inherited risk for colonic cancer is leading to a better understanding of this disease and is suggesting more directed preventive strategies.

Adenomatous Polyposis Coli↗

PubMedDate not supplied

Genetic screening: risk factors for breast cancer.

The field of cancer genetics is rapidly changing. Demand for information on genetic testing is increasing and persistent patient pressure is likely to result in increased NHS resource allocation. Cancer genetics clinics must change from small ad hoc research clinics to large throughput, patient-centred specialist services run jointly by doctors and clinical nurse specialists expert in cancer genetics and cancer medicine. We describe the development of a regional breast cancer genetics service in East Anglia based on the three-tier cancer care model outlined in the Calman report.

Breast Neoplasms↗

PubMed1999

Screening for hereditary cancer and genetic testing, epitomized by breast cancer.

The new genetics is having an impact on many areas of healthcare. Diversity in the genetic code accounts for differences in phenotypes between populations and it is becoming apparent that genetic differences may have a role in predisposition to and behaviour of disease. Genetic models suggest that there are two types of genetic predisposition to disease: the so-called high and low penetrance genes. At present, most of the impact on medicine has been from highly penetrant genes, and genetic testing for disease predisposition, particularly for diseases of late onset (e.g. certain cancers) is in its infancy. As a general statement, approximately 5-10% of common cancers are due to such highly penetrant genes. The category of genes that will become of increasing interest is that of the low penetrance genes. Often these are normal variations in genes that result in a slightly increased risk of disease. These are analogous to high blood pressure carrying an increased risk of cardiovascular disease. Once rapid genetic analysis is available for these types of genes, such analysis would be analogous to taking someone's blood pressure in a general practitioner's (GP's) surgery to identify individuals at increased risk of cardiovascular disease. This will produce a revolutionary change in the way we practise medicine. Genetic analysis will become faster and may therefore be more commonplace. It is possible to envisage an era when genetic analysis will become a routine part of primary care to identify changes in low penetrance genes that will confer a 'risk profile' for patients. This will then enable their primary care physicians to advise about primary prevention and even prescribe certain preventive drugs to decrease the risk of certain diseases occurring. This proactive rather than reactive style of practising medicine is potentially exciting, however it carries with it ethical, legal and social implications for how we deal with this new knowledge.

Adult↗

PubMed2000

[Genetic diagnosis for cancer--tumorigenesis and genetic alterations].

During malignant transformation, cancer cells acquire multiple genetic alterations that override the normal mechanisms controlling cellular proliferation. In brief, cancer is a disease of genetic abnormalities caused by hereditary and/or environmental factors. Genetic diagnosis for cancer can be divided into four categories: 1) pre-symptomatic diagnosis, 2) existence diagnosis, 3) property diagnosis-prognosis diagnosis and 4) genetic test for gene therapy. 1) For hereditary cancer families, pre-symptomatic diagnosis is available. Individuals with multiple cancers can be diagnosed by microsatellite instability(MSI) test using resected cancer tissues and by genotyping of mismatch repair enzymes. If the genotype abnormality is detected, the propositus can obtain early diagnosis and prevention of cancer, and genetic services of their siblings. 2) Using PCR technology, occult tumor cells can be detected from blood and other biological body fluids, as targets of chimeric transcripts and tissue-specific expressions. 3) Molecular properties of cancer cells are investigated for grading malignancy and therapeutic sensitivities. Using the molecular properties, prognosis of the patient can be estimated. 4) Following the genetic test results, the specific and superior gene therapy can be applied individually. Post-therapeutic monitoring is also available only by genetic test. After the genome project, the significance of single nucleotide polymorphisms(SNPs) related with cancer will be established, then tailor-made therapy and/or prevention will be applicable to individuals. The ultimate goal of genetic diagnosis would be the final priority to the phenotypic diagnosis.

Genetic Counseling↗

PubMed2001

Genetic and epigenetic changes in stomach cancer.

Genetic and epigenetic alterations of multiple cancer-related genes and molecules are implicated in the development and progression of human gastric carcinomas. Reactivation of telomerase, inactivation of p53 tumor suppressor gene, overexpression of cyclin E, and reduced expression of p27 KIP1 by disorganized degradation in proteasome are common events of both well-differentiated and poorly differentiated gastric adenocarcinomas. Inactivation of hMLH1 mismatch repair gene by CpG hypermethylation resulting in microsatellite instability, amplification of c-erbB2 oncogene, inactivation of APC tumor suppressor gene, and K-ras mutations are preferentially associated with well-differentiated gastric cancer. Conversely, reduction or loss of E-cadherin and catenins by both mutation and CpG hypermethylation and K-sam and c-met oncogene amplification are necessary for the development and progression of poorly differentiated or scirrhous gastric carcinomas. Interaction between cancer cells expressing c-met and hepatocyte growth factor from stromal cells is implicated in morphogenesis of gastric cancer.

Animals↗

PubMedDate not supplied

Dynamics of genetic instability in sporadic and familial colorectal cancer.

Genetic instability is a defining feature of human cancer. In colorectal cancer, two specific types of genetic instabilities have been identified: microsatellite instability (MIN) leads to a 1000-fold increase in the rate of subtle DNA changes, whereas chromosomal instability (CIN) enhances the rate at which gross chromosomal changes occur during cell division. In this paper, we develop a mathematical model for the dynamics of colon cancer initiation. We outline the processes and rate constants that determine the fraction of colon cancers where MIN or CIN mutations precede the inactivation of the first tumor suppressor gene. For a wide range of parameter values, we find support for the radical hypothesis that genetic instability initiates colonic tumorigenesis. We compare sporadic and hereditary forms of colorectal cancer.

Adenomatous Polyposis Coli↗

PubMed2001

Cell death associated with genetic prodrug activation therapy of colorectal cancer.

Genetic prodrug activation therapy (GPAT) is a form of cancer gene therapy that has potential use against tumours such as colorectal malignancy. The characterization of such therapies using laboratory models provides a basis for clinical trials. In this study the gene encoding Herpes Simplex Virus thymidine kinase (HSVtk) was delivered to colorectal tumour cells using an Adenoviral (Ad) vector in vitro. In this way the cells were made susceptible to killing with the prodrug ganciclovir to various degrees depending on cell infectability with Ad. Bystander killing effect appeared minimal both in vitro and when transduced cells were injected in vivo. Mechanisms of cell death, measured in vitro using anti-BrDU (DNA-break labelling) and propidium iodide staining variously showed a combination of apoptosis in the G1 cell cycle phase and late apoptotic or necrotic sub-G1 DNA fragmentation, depending on the tumour cell line. These findings suggest that gene therapy of colorectal cancer by GPAT gives rise to therapeutic forms of direct cell death, but requires improvements in transduction, and possibly immune augmentation.

Adenoviridae↗

PubMed2003

Genetic analysis of radiation-associated rectal cancer.

Genetic aberrations in radiation-associated colorectal cancer have not been studied in detail. We analyzed genetic aberrations in five rectal cancers that developed long after radiotherapy had been performed for cervical cancer. Microsatellite instability (MSI) in tumors was examined at five loci: D2S123, D3S966, TP53, DCC, and BAT26. Mutation of simple repeat sequences within the hMSH3, BAX, and transforming growth factor Beta type II receptor ( TGFBetaRII) genes was examined by polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP). Mutation of p53 exons 5-8 was examined by PCR-SSP and direct sequencing. Mutations of the K- ras gene were analyzed by two-step PCR. No MSI was found in tumor specimens at any of the loci examined, and no mutations in the target genes were observed. K- ras mutation was detected in two carcinomas, but not in their irradiated normal mucosa, while p53 mutation was observed in another two carcinomas, but not in their irradiated normal mucosa. Our results suggest that the radiation-associated rectal carcinomas examined in this study did not develop through the mutator phenotype pathway; rather, tumorigenesis was probably mediated through the multistep carcinogenesis pathway.

Aged↗

PubMed1992

[Genetic alterations in the genesis and development of ovarian cancer].

Genetic alterations of various cancers have been clarified by recent development of molecular biology. Multiple genetic alterations occur through the development of cancer. Both activation of proto-oncogenes and inactivation of tumor suppressor genes are important for the development of cancer. Alterations of oncogenes such as K-ras, c-erbB-2/HER-2/neu and c-myc, and those of tumor suppressor genes such as p53, RB and DCC have been reported in ovarian cancer. Allelic losses of the specific chromosomes, which suggest the existence of tumor suppressor genes on those chromosomes, also have been reported in ovarian cancer. Further studies on genetic alterations of ovarian cancer will clarify the mechanisms for the development of ovarian cancer and also will develop new methods for prevention, diagnosis and treatment in clinical.

Female↗

PubMed2001

[Progress in researches on the relationship between genetic polymorphisms of alcohol-metabolizing enzymes and cancers].

Genetic polymorphism of carcinogen-metabolizing enzymes is one of the important aspects of the genetic susceptibility to cancer. The enzymes involved in alcohol metabolism include mainly alcohol dehydrogenase(ADH), aldehyde dehydrogenase(ALDH) and cytochrome P450 2E1(CYP2E1), which all appear to be polymorphic. Several recent studies show that the genetic polymorphisms of alcohol-metabolizing enzymes are associated with some cancers such as liver cancer, stomach cancer and esophageal cancer. But there are also the inconsistent results.

Alcohol Dehydrogenase↗

PubMedDate not supplied

Genetic counseling in hereditary non-polyposis colorectal cancer.

Genetic counseling is a medical process aimed at providing information about disease risks for hereditary conditions. For adult-onset diseases, such as cancer, the main purpose consists in formulating probability estimates of disease appearance, along with details on preventive or follow-up measures. The process of genetic counseling has been substantially modified by the availability of molecular tests to identify mutant gene carriers. So far, 16 autosomal dominant genes associated with cancer susceptibility have been cloned. Four of these, which encode for components of the DNA mismatch repair machinery, have been implicated in hereditary non-polyposis colorectal cancer, one of the most common hereditary cancer syndromes. Genetic counseling and testing in hereditary non-polyposis colorectal cancer is associated with several problems that are common to other hereditary conditions (psychologic consequences, confidentiality, genetic "discrimination", testing of minors, prenatal diagnosis) and peculiar to the specific condition (incomplete penetrance, genotypic and phenotypic heterogeneity, limits of currently available tests). For such reasons, genetic testing should be performed in qualified research laboratories and restricted to highly selected families. In this way, pilot studies, involving both clinicians and researchers, can be undertaken with the aim of providing comprehensive results, potentially applicable to other cancer-predisposing conditions.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed2004

An update on the genetics of colorectal cancer.

Colorectal carcinoma (CRC) remains a frequent cause of cancer-associated mortality in the UK and still has a relatively poor outcome. Single gene defects account for up to 2-6% of cases, but twin studies suggest a hereditary component in 35%. CRC represents a paradigm for cancer genetics. Almost all the major-gene influences on CRC have been identified, and the identification of the remaining susceptibility alleles is proving troublesome. Only a few low-penetrance alleles, such as methylene tetrahydrofolate reductase C677T, appear convincingly to be associated with CRC risk. To identify the remaining CRC genes, parallel approaches, including strategies based on linkage and association and complementary analyses such as searches for modifier genes, must be employed. To gain sufficient evidence to prove that a gene is involved in CRC predisposition, it is probably necessary for multiple, adequately-powered studies to demonstrate an association with the disease, especially if the allelic variants have only a small differential effect on risk. It may also be possible to show how genes interact with each other and the environment, although this will be even more difficult. Accurate quantitation of the allele-specific risks in different populations will be necessary, but problematic, especially if those risks combine in a fashion which is not of a straightforward additive or multiplicative type. Without any good prior evidence of the nature of the remaining genetic influence on CRC, the possibility remains that this is a truly polygenic trait or that multiple, rare variants contribute to the increased risk; in these cases, identification of the genes involved will be very difficult. Despite these potential problems, the effectiveness of preventive measures for CRC, especially in high-risk individuals, means that the search for new predisposition genes is justified.

Colorectal Neoplasms↗

PubMed1992

Is cancer cytogenetics reducible to the molecular genetics of cancer cells?

Whether cancer cytogenetics can be reduced to the molecular genetics of cancer cells is a question that must be addressed in three domains, focusing on its ontological, methodological, and epistemological dimensions. The possibility of ontological reduction hinges on whether chromosomes have other important constituents than molecules. Although this must obviously be answered in the negative, it should be emphasized that both cytogenetic and recombinant DNA investigations provide us with very selective pictures of genomic organization. This is of concern because the higher order packing of DNA and its joining with other molecules to form chromosomal structures give rise to emergent properties, functional features that become manifest only at higher levels of complexity and that may not be deducible from the base pair composition of the DNA. A position of extreme methodological reductionism would in our context be that the best research strategy is always to investigate the genetic changes of tumor cells at the highest possible resolution level, as alterations of genes and, ultimately, as changes in DNA primary structure. There are two fundamental differences between cytogenetic and molecular genetic techniques that make this stance untenable. First, whereas cytogenetic investigations are open-framed (all chromosome aberrations are revealed), molecular genetic analyses are highly specific (only those aberrations are revealed that one tests for). Second, whereas the molecular approach determines the genotypic constitution of an idealized, average tumor cell, cytogenetic analysis is of real, individual cells. These may not necessarily be representative of the main population of the tumor, but at least whatever karyotypic differences exist between them are detected. Heterogeneity and clonal evolution within the tumor can thereby be assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Aberrations↗

PubMed2003

Distinct genetic and epigenetic changes in medullary breast cancer.

Genetic instability resulting in chromosome aneuploidy or mismatch repair deficiency characterizes cancer. Medullary carcinoma (MC) of the breast is a specific form of breast cancer with unique clinical, epidemiologic, and prognostic features, suggesting distinctive tumorigenic pathways. To investigate the nature of the genetic changes associated with MC we analyzed a series of 22 tumors. Chromosomal imbalances were assessed by comparative genomic hybridization (CGH) and mismatch repair (MMR) deficiency tested for through assessment of microsatellite instability (MSI) and expression of MLH1 and MSH2 genes. MMR deficiency was detected in only a small proportion of cases. The chromosomal copy number changes showed some similarities to BRCA1-associated tumors. A high level of BRCA1 promoter hypermethylation was detected, suggesting a possible role of this gene in MC development.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Genetic nurse counsellors can be an acceptable and cost-effective alternative to clinical geneticists for breast cancer risk genetic counselling. Evidence from two parallel randomised controlled equivalence trials.

This study compared genetic nurse counsellors with standard services for breast cancer genetic risk counselling services in two regional genetics centres, in Grampian region, North East Scotland and in Cardiff, Wales. Women referred for genetic counselling were randomised to an initial genetic counselling appointment with either a genetic nurse counsellor (intervention) or a clinical geneticist (current service, control). Participants completed postal questionnaires before, immediately after the counselling episode and 6 months later to assess anxiety, general health status, perceived risk and satisfaction. A parallel economic evaluation explored factors influencing cost-effectiveness. The two concurrent randomised controlled equivalence trials were conducted and analysed separately. In the Grampian trial, 289 patients (193 intervention, 96 control) and in the Wales trial 297 patients (197 intervention and 100 control) returned a baseline questionnaire and attended their appointment. Analysis suggested at least likely equivalence in anxiety (the primary outcome) between the two arms of the trials. The cost per counselling episode was 11.54 UK pounds less for nurse-based care in the Grampian trial and 12.50 UK pounds more for nurse-based care in Cardiff. The costs were sensitive to the grade of doctor (notionally) replaced and the extent of consultant supervision required by the nurse. In conclusion, care based on genetic nurse counsellors was not significantly different from conventional cancer genetic services in both trial locations.

Adolescent↗

PubMed2004

Genetic predisposition to cancer - insights from population genetics.

Individuals differ in their inherited tendency to develop cancer. Major single-gene defects that cause early cancer onset have been known for many years from their inheritance patterns, and inherited defects that have weaker effects on predisposition were also suspected to exist. Recent progress in cancer genetics has identified specific loci that are involved in cancer progression, many of which have key roles in DNA repair, cell-cycle control and cell-death pathways. Those loci, which are often mutated somatically during cancer progression, sometimes also contain inherited mutations. Recent genetic studies and quantitative population-genetic analyses provide a framework for understanding the frequency of inherited mutations and the consequences of these mutations for increased predisposition to cancer.

Age Factors↗

PubMedDate not supplied

Genetic alterations related to lymph node metastasis and peritoneal dissemination in epithelial ovarian cancers.

Genetic alterations are assumed to be necessary for the development and progression of ovarian cancer. However, the genetic alterations that occur during lymph node metastasis and peritoneal dissemination are poorly understood. In the present study, we used comparative genomic hybridization to detect genetic alterations in 30 tumors from patients with primary ovarian cancers and analyzed the associations of these genetic alterations with clinical stage and surgical pathological factors, such as histological grade, lymph node metastasis, and peritoneal dissemination. The total number of genetic alterations per tumor ranged from 0 to 39, with an average of 17.7 alterations per tumor. Among the genetic alterations in ovarian cancers, gains on chromosomes 8q and 3q and losses on chromosomes 17p, 18q, and 4q were observed frequently. Although the difference in total numbers of genetic alterations between early-stage tumors and advanced-stage tumors was not significant, the difference was significant when high-grade cancers were compared with low-grade cancers. Eight regions on seven chromosomes showed genetic alterations related to lymph node metastasis or peritoneal dissemination. Gain at 11q13-q14 and loss at 17q11.2-q21 were related not only to lymph node metastasis and peritoneal dissemination but also to clinical stage and histological grade.

Chromosomes, Human, Pair 11↗