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PubMed2002

Genetic testing for cancer predisposition.

The onslaught of genetic innovations in the past decade has resulted in the ongoing identification of a spectrum of genes, some of which, when mutated, result in cancer susceptibility. The impact of these discoveries on healthcare provides an opportunity to enhance health promotion and long-term health outcomes by identifying at-risk individuals before cancer develops. This provides the healthcare provider with the potential to intervene much earlier to either reduce the risk or diagnose a cancer early when the chances for effective treatment are greatest. Even though genetic testing is increasingly being employed clinically, there remains a gap between the technology and effective interventions. Genetic tests also provide information that is distinct from other tests used routinely in health promotion, because of the personal and family nature of the information. This results in unique clinical, ethical, legal, and social issues that further affect the effective diffusion of this technology clinically. This article provides an overview of the distinguishing characteristics of genetic testing, outlines the essential components of informed consent, and discusses the potential implications of testing on individuals' lives and the nurse's role in offering genetic testing.

Genetic Predisposition to Disease↗
PubMed2003

An investigation of genetic counselors' discussion of genetic discrimination with cancer risk patients.

Twenty-five genetic counselors who see familial cancer risk patients were interviewed about their definitions of genetic discrimination, perceptions of patient risk for discrimination, frequency and type of discrimination experienced by their patients, sources of information about discrimination, and what they tell patients about genetic discrimination. There was variability in participant definitions and content of discussions of genetic discrimination. Although 82% regarded risk to be low to theoretical, 40% reported possible instances of genetic discrimination, including insurance companies requiring results to cover procedures, denial of life/health insurance, social discrimination, and employment discrimination. Ninety-six percent of the sample reported always or almost always discussing genetic discrimination, and one or more of the following: insurance discrimination risks, protective legislation, no known cases positively documenting discrimination, strategies to avoid discrimination, and uncertainty of protective measures. The majority use current literature and research as information sources. Practice, policy, and research implications are discussed.

Adult↗
PubMed2005

Fighting cancer with vaccinia virus: teaching new tricks to an old dog.

Vaccinia virus has played a huge part in human beings' victory over smallpox. With smallpox being eradicated and large-scale vaccination stopped worldwide, vaccinia has assumed a new role in our fight against another serious threat to human health: cancer. Recent advances in molecular biology, virology, immunology, and cancer genetics have led to the design of novel cancer therapeutics based on vaccinia virus backbones. With the ability to infect efficiently a wide range of host cells, a genome that can accommodate large DNA inserts and express multiple genes, high immunogenicity, and cytoplasmic replication without the possibility of chromosomal integration, vaccinia virus has become the platform of many exploratory approaches to treat cancer. Vaccinia virus has been used as (1) a delivery vehicle for anti-cancer transgenes, (2) a vaccine carrier for tumor-associated antigens and immunoregulatory molecules in cancer immunotherapy, and (3) an oncolytic agent that selectively replicates in and lyses cancer cells.

Animals↗
PubMed2002

Genetics of childhood cancer.

In recent years, knowledge of the molecular genetics of childhood cancers has been increasing at an exponential rate. The study of the molecular mechanisms of oncogenesis has led to an understanding of the role that tumor suppressors, oncogenes, and deoxyribonucleic acid (DNA) repair genes play in development of the disease. Chromosomal translocations can lead to the disruption of growth regulatory genes or the formation of growth stimulatory fusion genes in leukemias and solid tumors. These alterations can occur sporadically or can be inherited, which often leads to cancer in children or young adults. Often, the presence of specific genetic alterations can be used to diagnose a cancer that otherwise would be difficult to verify. Genetic mutations also can be prognostic indicators and guide the treatment plan of the physician.

Ataxia Telangiectasia↗
PubMed2004

The genetics of skin cancer.

Recent advances in molecular genetics have led to a better understanding of the biological underpinnings of skin cancer formation. As with most cancers, the RB, p53, and RAS pathways appear to play prominent roles in the pathogenesis of several skin cancer types. Although various components of these pathways may be differentially altered in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma, the final biochemical expression of these defects may be the same. With the unraveling of these genetic mechanisms, a more targeted approach to diagnosis and treatment may be possible in the near future.

Carcinoma↗
PubMed1999

Replication of damaged DNA: molecular defect in xeroderma pigmentosum variant cells.

Individuals with Xeroderma pigmentosum (XP) syndrome have a genetic predisposition to sunlight-induced skin cancer. Genetically different forms of XP have been identified by cell fusion. Cells of individuals expressing the classical form of XP (complementation groups A through G) are deficient in the nucleotide excision repair (NER) pathway. In contrast, the cells belonging to the variant class of XP (XPV) are NER-proficient and are only slightly more sensitive than normal cells to the killing action of UV light radiation. The XPV fibroblasts replicate damaged DNA generating abnormally short fragments either in vivo [A.R. Lehmann, The relationship between pyramidine dimers and replicating DNA in UV-irradiated human fibroblasts, Nucleic Acids Res. 7 (1979) 1901-1912; S.D. Park, J.E. Cleaver, Postreplication repair: question of its definition and possible alteration in Xeroderma pigmentosum cell strains, Proc. Natl. Acad. Sci. U.S.A. 76 (1979) 3927-3931.] or in vitro [S.M. Cordeiro, L.S. Zaritskaya, L.K. Price, W.K. Kaufmann, Replication fork bypass of a pyramidine dimer blocking leading strand DNA synthesis, J. Biol. Chem. 272 (1997) 13945-13954; D.L. Svoboda, L.P. Briley, J.M. Vos, Defective bypass replication of a leading strand cyclobutane thymine dimer in Xeroderma pigmentosum variant cell extracts, Cancer Res. 58 (1998) 2445-2448; I. Ensch-Simon, P.M. Burgers, J.S. Taylor, Bypass of a site-specific cis-syn thymine dimer in an SV40 vector during in vitro replication by HeLa and XPV cell-free extracts, Biochemistry 37 (1998) 8218-8226.], suggesting that in XPV cells, replication has an increased probability of being blocked at a lesion. Furthermore, extracts from XPV cells were found to be defective in translesion synthesis [A. Cordonnier, A.R. Lehmann, R.P.P. Fuchs, Impaired translesion synthesis in Xeroderma pigmentosum variant extracts, Mol. Cell. Biol. 19 (1999) 2206-2211.]. Recently, Masutani et al. [C. Masutani, M. Araki, A. Yamada, R. Kusomoto, T. Nogimori, T. Maekawa, S. Iwai, F. Hanaoka, Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity, EMBO J. 18 (1999) 3491-3501.] have shown that the XPV defect can be corrected by a novel human DNA polymerase, homologue to the yeast DNA polymerase eta, which is able to replicate past cyclobutane pyrimidine dimers in DNA templates. This review focuses on our current understanding of translesion synthesis in mammalian cells whose defect, unexpectedly, is responsible for the hypermutability of XPV cells and for the XPV pathology.

Animals↗
PubMed1998

Genes and environment in the etiology of colorectal cancer.

Environmental factors, including diet, are important in the etiology of colorectal cancer. Genetic pathways of hereditary and sporadic bowel cancer are being elucidated. Highly penetrant mutations in certain genes, such as mismatch repair genes, play a major role in development of hereditary colorectal cancer, while interactions between low penetrance polymorphisms in carcinogen-metabolizing enzymes and environmental factors may identify susceptible subgroups and shed light on the etiology of sporadic colorectal cancers. In this review we summarize the current state of knowledge regarding the role of gene-environment interactions in development of colorectal cancer and discuss areas of particular promise, as well the limitations of these studies.

Colorectal Neoplasms↗
PubMed2001

Expression profiles of betaTRCP1 and betaTRCP2, and mutation analysis of betaTRCP2 in gastric cancer.

betaTRCP1 and betaTRCP2, components of the beta-catenin-ubiquitin ligase complex, are negative regulators of the WNT signaling pathway. We have previously isolated the betaTRCP2 gene, and detected betaTRCP2 in all gastric cancer cell lines examined. Here, expression profiles of betaTRCP1 and betaTRCP2 in various normal tissues and in primary gastric cancer were investigated. betaTRCP1 was predominant in small intestine, while betaTRCP2 was predominant in stomach. betaTRCP1 was expressed in gastric cancer cell lines MKN28, MKN45, MKN74, and KATO-III, but not in any cases of primary gastric cancer. betaTRCP2 was expressed in most cases of primary gastric cancer at almost the equal level in tumor and in non-cancerous portion of gastric mucosa. As betaTRCP2 was found to be the major betaTRCP expressed in gastric cancer, genetic alterations of betaTRCP2 in 7 gastric cancer cell lines and 12 cases of primary gastric cancer were investigated. A nucleotide substitution (Tright curved arrow C) at the nucleotide position 1486 of betaTRCP2 was identified in OKAJIMA cells, which lead to F462S amino acid substitution in the seventh WD-repeat domain. F462 was conserved among betaTRCPs derived from human, mouse, Xenopus laevis, and Drosophila melanogaster. As WD-repeats of betaTRCPs are the substrate-recognition motif of the beta-catenin-ubiquitin ligase, F462S amino-acid substitution might lead to beta-catenin stabilization, and might be implicated in carcinogenesis through activation of the WNT signaling pathway. This is the first report on comprehensive expression analyses of betaTRCP1 and betaTRCP2, and also on mutation analysis of betaTRCP2.

Blotting, Northern↗
PubMed2004

Genetic pathways of two types of gastric cancer.

Multiple genetic and epigenetic alterations in oncogenes, tumour-suppressor genes, cell-cycle regulators, cell adhesion molecules, DNA repair genes and genetic instability as well as telomerase activation are implicated in the multistep process of human stomach carcinogenesis. However, particular combinations of these alterations differ in the two histological types of gastric cancer, indicating that well-differentiated or intestinal-type and poorly differentiated or diffuse-type carcinomas have distinct carcinogenetic pathways. In the multistep process of well-differentiated-type carcinogenesis, the genetic pathway can be divided into three subpathways: an intestinal metaplasia-->adenoma-->carcinoma sequence, an intestinal metaplasia-->carcinoma sequence and de novo. In the multistep process of well-differentiated-type or intestinal-type gastric carcinogenesis, infection with Helicobacter pylori may be a strong trigger for hyperplasia of hTERT-positive 'stem cells' in intestinal metaplasia. Genetic instability and hyperplasia of hTERT-positive stem cells precede replication error at the D1S191 locus, DNA hypermethylation at the D17S5 locus, pS2 loss, RARbeta loss, CD44 abnormal transcripts and p53 mutation, all of which accumulate in at least 30% of incomplete intestinal metaplasias. All of these epigenetic and genetic alterations are common events in intestinal-type gastric cancer. An adenoma-->carcinoma sequence is found in about 20% of gastric adenomas with APC mutations. In addition to these events, p53 mutation and loss of heterozygosity (LOH), reduced p27 expression, cyclin E expression and the presence of c-met 6.0-kb transcripts allow malignant transformation from the above precancerous lesions to intestinal-type gastric cancer. DCC loss, APC mutations, 1q LOH, p27 loss, reduced tumour growth factor (TGF)-beta type I receptor expression, reduced nm23 expression and c-erbB gene amplification are frequently associated with an advanced stage of intestinal-type gastric cancer. The de-novo pathway for carcinogenesis of well-differentiated gastric cancer involves LOH and abnormal expression of the p73 gene that is responsible for the development of foveolar-type gastric cancers with pS2 expression. On the other hand, LOH at chromosome 17p, mutation or LOH of p53 and mutation or loss of E-cadherin are preferentially involved in the development of poorly differentiated gastric cancers. In addition to these changes, gene amplification of K-sam, and c-met and p27 loss as well as reduced nm23 obviously confer progression, metastasis and diffusely productive fibrosis. Mixed gastric carcinomas composed of well-differentiated and poorly differentiated components exhibit some but not all of the molecular events described so far for each of the two types of gastric cancer. Besides these genetic and epigenetic events, well-differentiated and poorly differentiated gastric cancers also organize different patterns of interplay between cancer cells and stromal cells through the growth factor/cytokine receptor system, which plays an important role in cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. Meta-analysis of epidemiological studies and animal models show that both intestinal and diffuse types of gastric cancer are equally associated with H. pylori infection. However, H. pylori infection may play a role only in the initial steps of gastric carcinogenesis. Differences in H. pylori strain, patient age, exogenous or endogenous carcinogens and genetic factors such as DNA polymorphism and genetic instability may be implicated in two distinct major genetic pathways for gastric carcinogenesis.

Cell Adhesion Molecules↗
PubMed2000

Likelihood of undergoing genetic testing for cancer risk: a population-based study.

BACKGROUND: Studies on public perceptions of genetic susceptibility testing for cancer risks are few and tend to focus on specific cancer risks of higher-risk populations, ignoring the general population and their perceived risk of getting any cancers. This study develops and tests a psychosocial model of the proximal and distal influences on likelihood of undergoing genetic susceptibility testing for cancer risk among a population-based sample. METHODS: The sample consisted of 622 adults aged 18-75 interviewed by telephone. The survey instrument included measures derived from the Health Belief Model and adaptations of existing measures from the literature. Data were analyzed using structural equation modeling techniques. RESULTS: The model suggested independent main effects for perceived benefits, perceived barriers, perceived susceptibility, and pessimism while simultaneously accounting for the effects of age, socioeconomic status, family history of cancer, and awareness of the existence of genetic susceptibility testing for cancer risk. The model explained 34% of the variance in likelihood. CONCLUSIONS: While perceived benefits, perceived barriers, perceived susceptibility, and pessimism may directly impact likelihood, they may also mediate the effects of age, socioeconomic status, family history of cancer, and awareness of cancer genetic susceptibility testing, on likelihood.

Adolescent↗
PubMed2001

The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches.

The recent completion of a rough draft of the human genome sequence has ushered in a new era of molecular genetics research into the inherited basis of a number of complex diseases such as cancer. At the same time, recent twin studies have suggested a limited role of genetic susceptibility to many neoplasms. A reappraisal of family and twin studies for many cancer sites suggests the following general conclusions: (a) all cancers are familial to approximately the same degree, with only a few exceptions (both high and low); (b) early age of diagnosis is generally associated with increased familiality; (c) familiality does not decrease with decreasing prevalence of the tumor-in fact, the trend is toward increasing familiality with decreasing prevalence; (d) a multifactorial (polygenic) threshold model fits the twin data for most cancers less well than single gene or genetic heterogeneity-type models; (e) recessive inheritance is less likely generally than dominant or additive models; (f) heritability decreases for rarer tumors only in the context of the polygenic model but not in the context of single-locus or heterogeneity models; (g) although the family and twin data do not account for gene-environment interactions or confounding, they are still consistent with genes contributing high attributable risks for most cancer sites. These results support continued search for genetic and environmental factors in cancer susceptibility for all tumor types. Suggestions are given for optimal study designs depending on the underlying architecture of genetic predisposition.

Environment↗
PubMed1993

Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer.

To examine genetic instability during carcinogenesis, we screened 171 carcinomas of the breast, liver, proximal colon, stomach, pancreas, uterine cervix, and ovary for replication error at four microsatellite marker loci on chromosome 2, 3, and 17. A significantly high incidence of genetic instability was observed in pancreatic (6 of 9 tumors) and gastric cancers (22 of 57 cases). In other types of carcinoma, the incidence of replication error-positive cases was relatively low (3-16%). Among gastric carcinomas, significantly more replication error-positive cases were observed in the poorly differentiated types (16 of 25 cases) than in well differentiated types (3 of 18) (P = 0.0023 by Fisher's exact test). Our results suggested that genetic instability is likely to play an important role in development of pancreatic and gastric cancers, particularly poorly differentiated adenocarcinomas.

Adenocarcinoma↗
PubMed1998

Genetic mapping of cancer susceptibility/resistance loci in the mouse.

Genetic linkage experiments using crosses between mouse inbred strains with an inherited predisposition and resistance to lung cancer make it possible to investigate the genetics of the complex inheritance of susceptibility and resistance to lung cancer. We have previously mapped a major locus (pulmonary adenoma susceptibility 1, Pas1) affecting inherited predisposition to lung cancer in mice onto chromosome 6, near Kras2. Appropriate crosses that include Pas1/+ mice provide a model system for identifying loci that can modify the lung cancer predisposition phenotype caused by Pas1. Using this approach, we mapped the pulmonary adenoma resistance 1 (Par1) locus on to mouse chromosome 11; this locus selectively inhibits lung tumor development in Pas1/+ animals and therefore behaves like a modulator gene of Pas1. More recently, we have mapped lung tumor modifier loci specifically affecting the initiation and progression of lung cancer. Thus experimental models provide an essential tool for the mapping of lung cancer susceptibility/resistance genes and for the subsequent cloning of candidate genes.

Adenoma↗
PubMed1981

Recent advances in cancer cytogenetics.

Recent technologic advances in human cancer genetics may provide valuable new tools in the diagnosis and prognosis of human cancer. Two new techniques, premature chromosome condensation (PCC), and the cloning of human tumor stem cells in agar, are described. It is suggested that as substantial progress occurs in our understanding of chromosome structure and function, additional clinically useful insights into the genetic basis and nature of cancer will be gained.

Chromosome Aberrations↗
PubMed1997

The genetics of colorectal cancer.

This article reviews the genetic alterations that are thought to play a role in the development of sporadic and hereditary forms of colorectal cancer. It also highlights their potential utility in clinical practice, especially in the field of presymptomatic diagnostic testing for hereditary forms of colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed1993

Genetic alterations in bladder cancer.

To see whether genetic alterations follow a sequence of events leading to bladder cancer progression, 60 paired bladder tumours and normal tissues were analysed with polymorphic DNA markers, correlating loss of heterozygosity (LOH) at candidate tumour suppressor gene sites with pathological indices of poor clinical outcome. Distinct genotypic patterns were associated with early and late stages of bladder cancer. 9q deletions were observed in all superficial papillary tumours (Ta) and almost all tumours invading the lamina propria (T1), suggesting that this event associates with the development of superficial bladder tumours. However, 3p, 5q, and 17p deletions were absent in the Ta tumours but were identified in invasive bladder cancers. Two genetic pathways characterise the evolution of superficial bladder tumours. 9qLOH was detected in most Ta tumours, but in only 43% of muscle invasive neoplasms. Our hypothesis is that certain chromosomal abnormalities have a defined role in bladder tumour development, whereas others correlate with pathological indices of poor clinical outcome.

Alleles↗
PubMed1997

Molecular genetics of colon cancer.

Colorectal cancer remains a major health problem. Few therapies are effective apart from surgery, and survival has increased little in recent years. This is despite the fact that screening by colonoscopy can potentially remove nearly all colorectal tumours before they become malignant. Molecular genetics has identified some inherited mutations (such as at APC and the mismatch repair loci) that predispose to colon cancer and some somatic mutations (such as at APC and p53) that cause sporadic colon tumours. We review the likely role of these and other genes in colorectal tumorigenesis. We also highlight areas of relative ignorance in colon cancer and emphasise that many important genes, especially those that cause invasion and metastasis, remain to be identified. Colorectal cancer is, however, a well characterised tumour, as regards both its natural history and its histopathology; there are consequently good prospects for advances in colon cancer genetics, with probable benefits for its treatment. We anticipate: (a) that new genes predisposing to colon tumours, including those conferring relatively minor risks, will be characterised; (b) genes and proteins important in invasion and metastasis will be identified; (c) the network of protein interactions in which molecules such as APC are involved will be elucidated; (d) large-scale studies of somatic mutations in tumours will provide accurate predictions of prognosis and suggest optimal therapeutic regimens; and (e) new potential targets for therapy will be identified. Whilst molecular genetics is by no means sufficient for progress in preventing and treating colon cancer, it is a necessary and central part of such advances.

Adenoma↗