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PubMed2007

Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions.

Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.

Aging↗
PubMed2006

Genetically engineered human cancer models utilizing mammalian transgene expression.

Cancer models are vital to cancer biology research, and multiple cancer models are currently available that utilize either murine or human cells, each with particular strengths and weaknesses. The ability to transform primary human cells into tumors through the expression of specific transgenes offers many advantages as a cancer model, including genetic malleability and the ability to transform specific cell types. Until recently, the conversion of primary human cells into tumors through transgene expression required the use of viral genetic elements, which unfortunately adds uncertainty regarding which cancer pathways are affected and how they are affected. In recent years multiple reports have described the transformation of primary human cells into tumors using only mammalian transgenes. This review focuses on these five cancer models, comparing the different cell types which were transformed into tumors and which transgenes were expressed, as well as the cancer pathways affected in the disparate models. These genetically-engineered human cancer models offer a valuable tool to complement existing cancer models and further cancer research.

Animals↗
PubMed2000

Physicians' attitudes towards mammography and prophylactic surgery for hereditary breast/ovarian cancer risk and subsequently published guidelines.

After a BRCA mutation has been identified in the context of hereditary breast/ovarian cancer (HBOC), mammographic screening and prophylactic surgery are two of the main options available to those responsible for the clinical management of healthy women. The aim of this study was to describe the attitudes of specialists towards the clinical management of women with an HBOC risk: this information was collected prior to the publication of the recent French guidelines. A random national sample of 1169 French surgeons, gynaecologists and obstetricians was surveyed using a mailed questionnaire, to which 700 of these physicians (60%) responded. When dealing with a BRCA mutated woman, 88.6% of the respondents said they would recommend mammographic screening, but only 27.1% would recommend that it should be carried out annually from the age of 30 years onwards, as recommended in the French guidelines; 10.9% would find it acceptable to propose prophylactic mastectomy from the age of 30 years, and 22.9% would find it acceptable to propose prophylactic oophorectomy from the age of 35 years. The specialists who agreed with recommending breast/ovarian cancer genetic testing also had more positive attitudes towards prophylactic mastectomy (adj OR = 3.4, 95% CI = 1.4-8.2), as did those who had previously recommended prophylactic mastectomy when gene testing was not yet available (adj OR = 2.06, 95% CI = 1.23-3.44). The respondents' attitudes towards prophylactic oophorectomy and mastectomy were significantly associated (adj OR = 3.9; 95% CI = 2.3-6.5). Previous recommendation of prophylactic mastectomy was associated (P < 0.01) with a higher level of knowledge of breast/ovarian cancer genetics and with medical practice in this field. French physicians' attitudes towards mammographic screening and prophylactic surgery were not in complete agreement with the subsequently published French guidelines, the impact of which has now to be considered. Constantly evolving knowledge about the efficacy of preventive intervention will give practitioners new elements to integrate into their counselling.

Attitude of Health Personnel↗
PubMed2005

The association between knowledge and attitudes about genetic testing for cancer risk in the United States.

Attitudes about genetic testing are likely to be an important determinant of uptake of predictive genetic tests among the general public. Several prior studies have suggested that positive attitudes about genetic testing may be inversely related to knowledge about genetic testing. We conducted a random-digit-dialing (RDD) telephone survey of 961 adults in the continental United States to determine the associations among knowledge of, attitudes about, and perceptions of eligibility for genetic testing for cancer risk. Knowledge about genetic testing for cancer risk was generally high, with a mean accuracy score of 72%. Attitudes about genetic testing for cancer risk were also generally positive, with 87% of respondents reporting genetic testing for cancer risk would be used to help doctors manage their health care and 85% to help scientists find cures for diseases. In contrast, 58% of respondents thought genetic testing for cancer risk would be used to prevent them from getting health insurance and 31% to allow the government to label groups as inferior. Twenty-nine percent of respondents thought they were currently eligible for testing. After adjustment for sociodemographic characteristics and family cancer history, higher knowledge was correlated with more positive attitudes about testing, but not with negative attitudes or perceptions of testing eligibility. Family history was positively associated with perceptions of eligibility (OR 3.49, 95% CI 2.36-5.18), and higher levels of education were inversely associated with perceptions of eligibility (OR 0.55, 95% CI 0.32-0.94 for comparison of college or higher vs. less than high school). These results suggest that most members of the general public are knowledgeable and have positive attitudes about genetic testing for cancer risk and that greater knowledge is correlated with more positive attitudes about the benefits of testing.

Adolescent↗
PubMed2006

On using a cancer center cancer registry to identify newly affected women eligible for hereditary breast cancer syndrome testing: practical considerations.

The goals of this research were to describe the process of identifying and recruiting individuals registered with a cancer center's cancer registry who were eligible to participate in cancer genetic research. This study specifically focused on younger women with personal and family cancer histories strongly suggestive of hereditary breast cancer syndromes, as determined by genetic counselor review. Of special interest was to determine the proportion of women from minority backgrounds who were (a) identifiable in this manner and (b) interested in genetic testing for hereditary breast cancer through a family cancer clinical research program. An initial query of the 292 cases of women newly affected with breast cancer and contained within the registry indicated that 124 met demographic eligibility criteria. The personal and family cancer histories of each of these women were then reviewed by a genetic counselor and the remaining, eligible patients (n = 31) were subsequently contacted by mail and telephone: approximately three-fifths (18/31) of these patients were White and two-fifths (13/31) were Black or of another racial background. Of the women who were sent one or more study-related mailings, 10% (3/31) were unreachable by telephone due to incorrect contact information, 32% (10/31) were reachable by telephone but unresponsive to messages left, 26% (8/31) had already participated in the family cancer program (i.e., were positive controls), 6% (2/31) were interested in participating in the program, 23% (7/31) were uninterested in participating in the program, and 3% (1/31) were later determined to be ineligible. Comparing the racial backgrounds of women who were either positive controls or interested in participating (i.e., "tester" category) to women who were either unreachable, nonresponsive, uninterested, or ineligible (i.e., "nontester" category), there was a nonsignificant trend for more non-White women to fall into the nontester than tester category, Fisher's Exact Test = .09. This work underscores practical steps in planning and carrying-out cancer genetic testing research among women newly affected with breast cancer and members of special populations. It also underscores the role that genetic counseling professionals play in this process.

Adult↗
PubMed1999

Counseling your patient about heritable breast cancer.

The baseline frequency of breast cancer increases after age 30 from about 1% to about 10% by age 90. Breast cancer gene mutations cause much higher risks. Risks are nearly as high if two or more first-degree relatives (mother, sisters) had breast cancer when less than 50 years old. Risks are also elevated by occurrence of breast cancer at young ages in second-degree relatives (grandmothers, aunts). Certain rare syndromes are also associated with higher risks of breast cancer. Genetic testing for breast cancer gene mutations and for some of the syndromes is available but mutational heterogeneity limits its usefulness. Counseling about these aspects of breast cancer should be within the purview of any physician who manages patients who are at risk. The medical geneticist can assist in recognizing rare syndromes, identifying patients whose risks merit consideration of genetic testing or of prophylactic surgery, and in counseling in complex cases.

Adolescent↗
PubMed1995

Mosaicism: the embryo as a target for induction of mutations leading to cancer and genetic disease.

Mosaicism, the existence of "patches" of cells with a genetic constitution that differs from that of other cells of an organism, has been observed in both germinal and somatic tissues of several species, including humans. Mutational events occurring during early embryogenesis can give rise to an organism with a significant number of cells with the mutant genotype in one or more tissues. If this event occurs in a precursor of the germ cells, the mutation can be transferred to subsequent generations. In the F1 generation, this event will usually be perceived as a de novo germinal mutation rather than a transmitted variant allele, unless significant effort is directed toward detecting the mosaicism. Similarly, mutations in oncogenes and tumor-suppressor genes in proliferating somatic cells can generate populations of cells that are at increased risk of transforming into tumor cells. The number of potential preneoplastic cells is larger when the mutagenic event occurs in early development than if it occurs in the mature adult. Experimental data confirm that treatment of the developing embryo or fetus with carcinogenic and mutagenic agents increases the cancer incidence in these animals and the frequency of mutations in the offspring of the animals that were exposed in utero. The available data are conclusive that the developing organism is at risk from exposure to mutagenic and carcinogenic agents. However, the data are insufficient to estimate the level of risk associated with exposures in utero, relative to either the background (spontaneous) level of risk or risk associated with similar exposures to the adult organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Chromosomal radiosensitivity, cancer predisposition and response to radiotherapy.

AIM: This paper briefly summarizes the research on this topic, undertaken in the Department of Cancer Genetics, Paterson Institute for Cancer Research, Manchester, England, over the previous 6 years. PATIENTS AND METHOD: Patients with the recessively-inherited disease, ataxia-telangiectasia (A-T), who are cancer-prone and suffer severe reactions after radiotherapy, also have highly radiosensitive cells, particularly when chromosome damage is used as the measure of radiosensitivity. Enhanced chromosomal radiosensitivity is also a feature of many other cancer-prone disorders. We have investigated the possible role of such radiosensitivity as a marker of cancer predisposition and response to radiotherapy in the general population. RESULTS: We found that 42% (57/135) of breast cancer patients exhibit chromosomal radiosensitivity when lymphocytes are irradiated in the G2 phase of the cell cycle, compared with 6% (6/105) of healthy controls (Figure 1). These figures are much higher than the estimated frequencies of carriers of the ataxia-telangiectasia gene (heterozygotes) amongst breast cancer patients (< 5%) and controls (0.5%). We have also obtained evidence of heritability of G2 sensitivity by studying relatives of breast cancer cases (Figures 2 and 3). The pattern of inheritance is relatively simple and attributable to 1 or 2 genes segregating in each family (Figure 4). In a prospective study of 123 breast cancer patients, 9 (7%) had severe acute reactions to radiotherapy and their mean G2 sensitivity was significantly greater (p = 0.001) than that of the remaining patients (Figure 5). In 16 patients with adverse acute reactions we found no mutations of the ataxia-telangiectasia gene (ATM). Using another chromosomal assay (micronucleus induction in G0 lymphocytes) we found that the mean radiosensitivity of patients with severe late reactions was higher than that of normal reactors. For example, 8 patients with severe fibrosis were more sensitive (p = 0.055) than 39 patients with a normal response (Figure 6). However, the discriminatory power of these chromosomal assays is too low for them to be used alone in a clinical setting. CONCLUSION: Our results provide good evidence that genes other than ATM, that confer chromosomal radiosensitivity, are involved in low penetrance predisposition to breast cancer in a high proportion of cases and contribute to adverse reactions after radiotherapy.

Ataxia Telangiectasia↗
PubMed1996

[Oncogenes and anti-oncogenes: the genetics of cancer].

Oncogenes and anti-oncogenes form two families of genes. If abnormal both may induce malignancies. They are distinguished, however, by two components. Oncogenes play a certain role in a given period of development (mainly during organogenesis). As soon as function has been completed they are inactivated. Aberrant reactivation even of one allele may induce tumors in different tissues independent of age. Anti-oncogenes on the other hand protect the organism, functioning mainly at the level of cell cycle regulation. Because one allele is sufficient for sustaining of adequate function both alleles of the anti-oncogene must be destroyed before tumor development is possible. Such a tumor will be tissue- and age-specific.

Embryonic and Fetal Development↗
PubMed2004

Clinical applications of genetics in sporadic cancers.

OBJECTIVES: To describe how genetic information shapes our understanding of carcinogenesis; how genetic information influences recommendations for cancer screening, prevention, diagnosis, and treatment; and how genetic information may affect the prognosis of patients with cancer and the monitoring of anticancer treatment. DATA SOURCES: Medical and nursing literature, textbooks, Internet websites. CONCLUSION: The Human Genome Project has taken oncology one step further toward accurate diagnosis and treatment of many forms of cancer. There are many genetic traits that can be associated with increased cancer risk, diagnosis, and selection of treatments. IMPLICATIONS FOR NURSING PRACTICE: Oncology nursing practice is directly affected by the developments of medical genetics. The information gained can be used by nurses at all stages of the cancer continuum when administering these new therapies.

Antineoplastic Agents↗
PubMed2006

Colorectal cancer and genetic alterations in the Wnt pathway.

In colorectal tumours, Wnt pathway genetics continues to be dominated by mutations in the adenomatous polyposis coli (APC) gene. Germline mutations cause familial adenomatous polyposis and at least two-thirds of sporadic colorectal tumours also acquire APC mutations, quite possibly as the initiating events in tumorigenesis. These mutations almost always cause loss of the C-terminal functions of the APC protein - probably involved in microtubule binding, cell polarity and chromosome segregation - and deletion of the SAMP repeats that are important for binding to axin and formation of the beta-catenin phosphorylation complex. The truncated APC proteins are, in general, stable and almost certainly retain some activity in beta-catenin binding. The 'two hits' at APC are coselected so as to produce an optimal activation of Wnt signalling (just-right hypothesis). In a minority of colorectal tumours, Wnt activation can occur through mutations that affect phosphorylation sites within exon 3 of beta-catenin, causing protein stabilization. In other tumours, epigenetic transcriptional silencing or mutation of the secreted frizzled-related proteins may modulate Wnt levels. Mutations in the Wnt components AXIN1, AXIN2 and TCF4 have been found in microsatellite-unstable colon cancers, but it is not clear in every case whether these changes are functional. Therapeutic modulation of the Wnt pathway remains an attractive therapeutic possibility for colorectal carcinomas.

Adenomatous Polyposis Coli↗
PubMed1996

p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and cancer risk assessment.

Carcinogenesis is a multistage process involving the inappropriate activation of normal cellular genes to become oncogenes, e.g., ras, and the inactivation of other cellular genes called tumor suppressor genes. p53 is the prototypic tumor suppressor gene that is well suited as a molecular link between the causes of cancer, i.e., carcinogenic chemical and physical agents and certain viruses, and the development of clinical cancer. The p53 tumor suppressor gene is mutated in the majority of human cancers. Genetic analysis of human cancer is providing clues to the etiology of these diverse tumors and to the functions of the p53 gene. Some of the mutations in the p53 gene reflect endogenous causes of cancer, whereas others are characteristic of carcinogens found in our environment. In geographic areas where hepatitis B virus and a dietary chemical carcinogen, aflatoxin B1, are risk factors of liver cancer, a molecular signature of the chemical carcinogen is found in the mutated p53 gene. A different molecular signature in the p53 gene is found in skin cancer caused by sunlight. Because mutations in the p53 gene can occur in precancerous lesions in the lung, breast, esophagus, and colon, molecular analysis of the p53 gene in exfoliated cells found in either body fluids or tissue biopsies may identify individuals at increased cancer risk. p53 mutations in tumors generally indicate a poorer prognosis. In summary, the recent history of p53 investigations is a paradigm in cancer research, illustrating both the convergence of previously parallel lines of basic, clinical, and epidemiologic investigation and the rapid translation of research findings from the laboratory to the clinic.

Animals↗
PubMed2007

Successful cancer vaccine therapy for carcinoembryonic antigen (CEA)-expressing colon cancer using genetically modified dendritic cells that express CEA and T helper-type 1 cytokines in CEA transgenic mice.

This study was designed to determine whether the vaccination of genetically modified dendritic cells (DCs) simultaneously expressing carcinoembryonic antigen (CEA), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 12 (IL-12) can overcome the peripheral T-cell tolerance to CEA and thereby elicit a therapeutic response in CEA transgenic mice. CEA transgenic mice were immunized once by subcutaneous injection with DCs adenovirally transduced with CEA and T helper-type 1 cytokine genes. The cytotoxic activity of spleen cells against CEA-expressing tumors, MC38-CEA, in the mice immunized with DCs expressing CEA (DC-AxCACEA) was higher than that in those immunized with DCs-AxCALacZ (p < 0.0001), and was augmented by the cotransduction with the GM-CSF/IL-12 gene (p < 0.05). The vaccination with DC-AxCACEA/GM-CSF/IL-12 could elicit a more potent therapeutic immunity than the vaccination with DC-AxCACEA in subcutaneous tumor models (p < 0.0001), and 4 of 5 mice showed a complete eradication of the subcutaneous tumors in these vaccination groups. Even in a large tumor model, this vaccination therapy completely eliminated the subcutaneous tumors in all mice. This antitumor activity mostly vanished with the depletion of CD8(+) T cells and NK cells in vivo and was completely abrogated with the depletion of CD4(+) T cells. A histopathological examination showed no evidence of an autoimmune reaction. No other adverse effects were observed. This vaccination strategy resulted in the generation of highly efficient therapeutic immune responses against MC38-CEA in the absence of autoimmune responses and demonstrated no adverse effects, and may therefore be useful for future clinical applications as a cancer vaccine therapy.

Animals↗
PubMedDate not supplied

Enhancing the readability of materials describing genetic risk for breast cancer.

BACKGROUND: The number of individuals contemplating genetic testing is increasing, but the current materials and overall subject matter remain complex and not easily understood by many. The goal of this project was to evaluate efforts to revise and increase the readability of an existing information packet describing genetic risk for breast cancer. METHODS: Evaluation was conducted in two stages through two related studies. In Study 1, a focus group of multiethnic breast cancer survivors was assembled to obtain feedback on images included in the revised breast cancer genetics information packet. In Study 2, African American adult students in a literacy program evaluated the revised images (based on the feedback of the focus group in Study 1) and text of the information packet and provided ratings on readability, format, and appearance. RESULTS: Responses from Study 1 participants suggested that some of the images created for the packet needed to be clearer in the concepts they were intended to convey. In Study 2, ratings of adult learners suggested difficulty with word comprehension in spite of the inclusion of definitions and a glossary. The reading level achieved was markedly lower than the college reading level required by the original information packet and other patient-directed cancer genetics materials. CONCLUSIONS: Although efforts to clarify written materials in order to better serve patients with low literacy received generally favorable responses, continued efforts to create more user-friendly patient education materials are warranted.

Adult↗
PubMed2004

Estrogen receptor genotypes and haplotypes associated with breast cancer risk.

Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), approximately O.4; 95% confidence interval (CI), 0.2-0.8; P < 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2-3.8; P < 0.05). A unique risk haplotype was present in approximately 7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2-2.4; P < 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.

Base Sequence↗
PubMedDate not supplied

Bringing threat to the fore: participating in lifelong surveillance for genetic risk of cancer.

PURPOSE/OBJECTIVES: To explain how patients with multiple endocrine neoplasia type 2a (MEN2a) and family members conceptualize participation in lifelong surveillance in genetic cancer care. DESIGN: Qualitative naturalistic inquiry. SETTING: Northeastern United States. Data were collected during interviews in informants' homes. SAMPLE: 12 adult patients and 9 family members were recruited purposively through endocrinology clinics at two East Coast medical centers. METHODS: A grounded theory design was used. Subjects completed a demographic questionnaire and were interviewed on two occasions. In-depth interviews were audiotaped. The core concept and process variables emerged through three levels of narrative content analysis, theoretical sampling, and constant comparison. The generated theory was presented to the participants for validation. MAIN RESEARCH VARIABLES: The basic psychological issue associated with participation in lifelong surveillance and the psychosocial processes used by individuals to deal with the issues. FINDINGS: MEN2a patients and family members experience surveillance as a (Re)Minding of a threat to health. Once threat is brought to the fore, participants interpret the meaning and negotiate control of the impact of the diagnosis, related events, and consequences. Meaningful information from surveillance activities is incorporated into participants' self-image and daily lives through a process of (Re)Integration. The genetic nature of MEN2a did not emerge as a significant subcategory in relation to the core variable. CONCLUSIONS: Finding meaning in the outcomes of surveillance events is a psychosocial process that is central to participation in lifelong surveillance. Genetic predisposition to cancer was a peripheral concern to subjects as they dealt with surveillance issues. IMPLICATIONS FOR NURSING: This investigation provides a model for the development of a grounded theory for understanding how people with other genetic cancer syndromes participate in lifelong surveillance.

Adrenal Gland Neoplasms↗