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PubMed2005

Accurate genotyping from paraffin-embedded normal tissue adjacent to breast cancer.

Genetic polymorphism analysis for disease risk is widely used in epidemiology studies; blood or oral cavity cells are the most widely used source of DNA. However, these types of samples are not always available, particularly for studies that were conducted years ago. An alternative potential source of patient DNA exists in the form of paraffin-embedded normal tissue adjacent to tumor samples, which are collected and stored routinely for clinical use. The use of such samples can be conceptually problematic, however, due to the presence of field cancerization in the surrounding normal tissue, with the possible presence of chromosomal loss. Specifically, loss of heterozygosity (LOH) might bias the genotyping results and cause genotype misclassification. However, field cancerization and LOH might not be an issue because LOH is not easily found unless there is careful microdissection of only tumor cells (leaving stromal, inflammatory and fat cells), for example, laser-capture microdissection. In this study, we set out to determine the degree of genotype misclassification from normal tissues adjacent to tumors, if any, by comparing these results with blood genotyping. We examined samples from 106 subjects with breast cancer, analyzing five different genotypes selected from regions commonly known to have LOH in breast cancer. These genotypes were methylenetetrahydrofolate reductase (MTHFR), oxoguanosine glycosylase 1 (hOGG1), dopamine beta-hydroxylase (DBH), dopamine receptor D2 (DRD2) and NAD(P)H dehydrogenase quinone 1 (NQO1), conducted by using real-time PCR and TaqMan genotyping analyses. We found that among these five genotypes and 106 comparisons, there was a 100% concordance for genotyping from normal tissue adjacent to tumor and from blood. Our findings indicate that the use of adjacent normal tissues provides accurate genotyping results with high specificity. Although this study only used breast tumor samples, and may be applicable only to breast cancer studies, we expect the results to be applicable to other types of cancers also.

Biopsy↗
PubMed1998

A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers.

Genetic and biochemical studies in lower eukaryotes have identified several proteins that ensure accurate segregation of chromosomes. These include the Drosophila aurora and yeast Ipl1 kinases that are required for centrosome maturation and chromosome segregation. We have identified two human homologues of these genes, termed aurora1 and aurora2, that encode cell-cycle-regulated serine/threonine kinases. Here we demonstrate that the aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies. We propose that aurora2 may be a target of this amplicon since its DNA is amplified and its RNA overexpressed, in more than 50% of primary colorectal cancers. Furthermore, overexpression of aurora2 transforms rodent fibroblasts. These observations implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome-associated proteins as novel targets for cancer therapy.

3T3 Cells↗
PubMed2005

Loss of heterozygosity at 17p13.3-ter, distal to TP53, correlates with negative hormonal phenotype in sporadic breast cancer.

Genetic alterations on chromosome 17p are frequent in a variety of human malignancies such as sporadic breast carcinomas. The clinico-pathological significance of it remains to be elucidated. The purpose of this study was to explore whether the allelic loss (LOH) in 17p13.3, which is suggested by the presence of tumour suppressor genes, independent of TP53, are related to current clinico-pathological criteria for characterising breast cancer. A group of sporadic breast carcinomas, with no alteration in TP53 locus, were analysed for the presence of LOH in D17S34 and D17S30/5 loci, mapped to the 17p13.3 region, distinct from and telomeric to TP53. LOH by at least one marker was observed in 13 of 47 informative cases (27.6%). Clinicopathological parameters such as age, menopausal status, histological type, tumour size, nodal status, grading, ploidy, labelling index, S-phase fraction and hormonal phenotype, were evaluated. LOH at distal 17p13.3 significantly correlated with the absence of oestrogen receptors (ER) (P=0.018), progesterone receptors (PgR) (P=0.009) and concordant absence of either ER or PgR (P=0.006). This may provide a basis for speculation as to the function of the putative tumour suppressor genes in 17p13-ter in sporadic breast cancer.

Breast Neoplasms↗
PubMed1992

Genetics and cancer.

In the past year we have witnessed significant progress in understanding the molecular basis of cancerogenesis and in identifying the genetic determinants of susceptibility to cancer. In particular, the finding that the same tumor suppressor genes play a pathogenic role in both the inherited and the sporadic forms of some childhood tumors has suggested that this gene class may also be involved in adult tumors derived from inherited familial cancer syndromes. The identification of the gene defect underlying the Li-Fraumeni syndrome, a germline mutation of the tumor suppressor gene p53, has fully confirmed that suggestion. Three other genes associated with the inherited cancer syndromes neurofibromatosis type I (NF-1) and familial adenomatous polyposis have been cloned and partially characterized. In addition to these genes, which have a relatively high penetrance and contribute directly to tumorigenesis, other genes that lead to cancer as a secondary effect seem to act in determining an individual's overall cancer risk. The latter genes are most likely related to defective processes of DNA repair or to regulation of carcinogen metabolism. In this context the analysis of models of murine strains with different genetic susceptibility to cancer of various organs may be a useful tool for unveiling the genetic basis for cancer susceptibility in individuals.

Animals↗
PubMed1995

Genetics in cancer care: confronting a Pandora's Box of dilemmas.

PURPOSE/OBJECTIVES: To provide an overview of sociopolitical, bioethical, and psychological issues emerging from the application of genetic technologies in cancer care in the United States and to provoke oncology nurses to consider the impact that advances in genetics may have on their practice. DATA SOURCES: Published professional articles, tests, and proceedings as well as government and lay publications. DATA SYNTHESIS: This article reviews underlying sociopolitical issues and forecasts bioethical dilemmas and psychological responses likely to emerge from expanding genetic screening and treatment options in oncology. The sociopolitical issues revolve around individual rights, the role of government, and the influence of religious dogma and public perception. The bioethical dilemmas fall within a framework of five scenarios, and a range of psychological responses are described. CONCLUSIONS: Significant changes will occur in cancer care as a result of advances in genetic technology. These changes will be accompanied by a new set of dilemmas in clinical practice and by as yet undescribed psychological responses. In addition to building a knowledge base relevant to these new technologies, oncology nurses must anticipate the new dilemmas and be prepared to manage the emotional responses of their patients. NURSING IMPLICATIONS: Nurse are in a strategic position to make significant contributions to the genetics data base by designing and conducting research to describe the ethical dilemmas and patient/family responses engendered as genetic science is integrated into cancer care.

Bioethics↗
PubMed1999

Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers.

Genetic instability is a key mechanism of tumorigenesis, and the instability exists at two distinct levels, the nucleotide and the chromosome levels. Disruption of the mitotic spindle checkpoint is one of the underlying mechanisms leading to aneuploidy and alterations of hsMAD2 and hBUB1, assumed to take part in the spindle checkpoint in human cells, have been found to be associated with chromosomal instability in some tumor cell lines. Therefore, we investigated the mutational status of the hsMAD2 and hBUB1 genes in 32 sporadic digestive tract cancers by reverse transcription-polymerase chain reaction-single strand conformation polymorphism analysis. The entire coding sequence of the hsMAD2 gene, and conserved regions (codons 21-152 and codons 732-1043) presumed to be functionally important in the hBUB1 gene were analyzed. Mutation of the hsMAD2 gene was not observed at all and missense mutation of the hBUB1 gene was noted in one rectal cancer case. Sequencing analysis revealed an AGT-to-GGT missense mutation, substituting glycine for serine, at codon 950, which is conserved between budding yeast and human. These results indicate that mutations of the hsMAD2 and hBUB1 genes are very rare and presumably play a very restricted role in tumor development of sporadic cancers.

Adenocarcinoma↗
PubMed2005

Ethnicity, genetics, and breast cancer: media portrayal of disease identities.

OBJECTIVE: To describe, compare, and analyze how the risk of breast cancer is framed in newspapers directed towards an ethnic minority population (Jewish) with higher risk of inherited breast cancer compared with newspaper coverage for the general population (Anglo-Canadian) without this risk. DESIGN: This investigation utilized a mixed methods (quantitative and qualitative) approach. The design emphasized a content analysis conducted on ethnically specific and non-ethnic newspaper articles. RESULTS: It is noteworthy that the 'Jewish' newspapers devote a substantially larger proportion of articles on breast cancer to genetic risk as the key risk factor for this disease. Articles in the Jewish newspapers tend to link being a Jewish woman with being at risk for a diagnosis of breast cancer. This ethnic 'identity' is reinforced through the repeated association of Jewish heritage and genetic breast cancer risk at the exclusion of other known risk factors. This isolated genetic link to breast cancer is not a message that is replicated within the provincial newsprint articles. CONCLUSIONS: These findings assist in the facilitation of prevention and treatment of those with or at risk of breast cancer. The health policy implications of this portrayal as well as suggestions for change are considered.

Breast Neoplasms↗
PubMed1995

Direct gene transfer for treatment of human cancer.

Genetic instability within malignant cells gives rise to mutant proteins which can be recognized by the immune system. Recognition of tumor-associated antigens by T lymphocytes could thus contribute to the elimination of neoplastic cells. We have developed a molecular genetic intervention for the treatment of malignancies based upon the knowledge that foreign major histocompatibility complex (MHC) proteins expressed on the cell surface are efficient at stimulating an immune response. Expression of this foreign MHC gene within tumors induced a cytotoxic T cell response to the introduced gene. More importantly, the immune system recognized tumor-specific antigens on unmodified tumor cells as foreign. Growth of the tumors diminished, and in many cases, there was complete regression. This research provides evidence that direct gene transfer in vivo can induce cell-mediated immunity against specific gene products, and offers the potential for effective immunotherapy for the treatment of cancer and infectious diseases in man. Our laboratory conducted a phase I clinical trial to determine the safety and efficacy of this treatment in humans. These studies suggest that direct gene transfer provides a safe and feasible approach for the treatment of human cancer. More recent developments using combination gene therapy and the initiation of a second human trial with improvements on this technology have been implemented. Finally, we have begun to define mechanisms of resistance to immune recognition by established malignancies.

Animals↗
PubMed2002

APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers.

Genetic alterations serve as beacons for the involvement of specific pathways in tumorigenesis. It was previously shown that 5% of prostate tumors harbor CTNNB1 mutations, suggesting that this tumor type may involve a deregulated APC/CTNNB1 pathway. To explore this possibility further, we searched for mutations in genes implicated in this pathway in 22 samples that included cell lines, xenografts, and primary tumors. We identified seven alterations: two in CTNNB1, three in APC, and two in hTRCP1 (also known as BTRC) which controls the degradation of CTNNB1. Alterations in the CTNNB1 regulatory domain, APC, and hTRCP1 were mutually exclusive, consistent with their equivalent effects on CTNNB1 stability. These results suggest that CTNNB1 signaling plays a critical role in the development of a significant fraction of prostate cancers. Moreover, they provide the first evidence that hTRCP1 plays a role in human neoplasia.

Animals↗
PubMed2004

Application of comparative functional genomics to identify best-fit mouse models to study human cancer.

Genetically modified mice have been extensively used for analyzing the molecular events that occur during tumor development. In many, if not all, cases, however, it is uncertain to what extent the mouse models reproduce features observed in the corresponding human conditions. This is due largely to lack of precise methods for direct and comprehensive comparison at the molecular level of the mouse and human tumors. Here we use global gene expression patterns of 68 hepatocellular carcinomas (HCCs) from seven different mouse models and 91 human HCCs from predefined subclasses to obtain direct comparison of the molecular features of mouse and human HCCs. Gene expression patterns in HCCs from Myc, E2f1 and Myc E2f1 transgenic mice were most similar to those of the better survival group of human HCCs, whereas the expression patterns in HCCs from Myc Tgfa transgenic mice and in diethylnitrosamine-induced mouse HCCs were most similar to those of the poorer survival group of human HCCs. Gene expression patterns in HCCs from Acox1(-/-) mice and in ciprofibrate-induced HCCs were least similar to those observed in human HCCs. We conclude that our approach can effectively identify appropriate mouse models to study human cancers.

Animals↗
PubMed1998

Assessment of family cancer history collection and utilization in patient care.

OBJECTIVES: This study was conducted to determine whether patients and accompanying persons visiting the Gynecologic Oncology Clinic were aware if a family cancer history was recorded and utilized in their medical care; whether they were aware of the importance of a family cancer history, and whether they would like to learn more about familial cancer. METHODS: Sixteen- and 17-item self-report questionnaires were administered to patients and their accompanying persons, respectively, who were visiting the Gynecologic Oncology Clinic. All responses were anonymous. RESULTS: Two hundred forty-four patient questionnaires and 114 accompanying person questionnaires were completed. Seventy-eight percent of the patients and 70% of the accompanying persons replied that a physician had inquired about their family history of cancer. Only 40% of those patients and 70% of those accompanying persons (31 and 49% of total patients and accompanying persons, respectively) replied that the inquiry was by their family physician. Sixty-seven percent of these patients and 63% of these accompanying persons reported that a written record was made of the family history. Thirty-one percent of the patients and 28% of accompanying persons knew that their family cancer history information had been used to aid in their medical care. Eighty-eight percent of the patients and 83% of the accompanying persons reported the occurrence of at least one relative with cancer; however, only 44% of the patients and 35% of the accompanying persons replied that a health care provider had ever provided teaching about the importance of a family cancer history. Seventy-five percent of the patients and 73% of the accompanying persons indicated that they would like to learn more about hereditary cancer and cancer genetics. CONCLUSIONS: This study demonstrates that patients desire information about cancer genetics and hereditary cancer. Therefore, health care providers should provide better education and information to their patients as well as improve their family history-taking skills.

Journal Article↗
PubMed1997

Expression genetics in cancer: shifting the focus from DNA to RNA.

Expression genetics is a conceptually different approach to the identification of cancer-related genes than the search for mutations at the genome level. While mutations lie at the heart of cancer, at least in its early stages, what is recognized here are phenotypic changes usually many steps removed from the initiating mutation. Classically cancer geneticists have concentrated on genomic changes and have ignored the productive potential of examining downstream events based on screening for differential gene expression between tumor cells and well matched normal counterparts. Genes involved in cancer affect the normal functions of many cellular processes: not only proliferation but cell-cell and cell-matrix interactions, DNA repair, invasion and motility, angiogenesis, senescence, apoptosis, and others. Yet very few cancer-related genes affecting these processes have been identified in human cancers by classical methods to find mutated genes despite enormous efforts. I report here our success in readily isolating more than 100 candidate tumor suppressor genes from human tissue, estimated to represent roughly 20% of the total genes recoverable by this approach. Half of the genes are unknown and the other half include representatives of most known cancer processes. Because their expression is lost during cancer progression, they may be useful tumor markers for diagnosis and prognosis. Because these genes are not mutated, they provide opportunities for pharmacological intervention by inducing their reexpression.

Breast Neoplasms↗
PubMed2000

Accuracy of family history of cancer: clinical genetic implications.

Family medical history is the cornerstone of clinical genetic diagnosis and management in cases of familial cancer. The soundness of medical decisions can be compromised if reports by the family on affected relatives are inaccurate. Although very time consuming, family medical histories are therefore routinely verified. To investigate whether such verification is clinically justified, we retrospectively analysed the accuracy of a consecutive series of 383 tumour reports from counsellees on 120 families in our clinic. We evaluated these families for the impact of verification on clinical genetic diagnosis and management. Accuracy according to cancer type showed marked variation, ranging from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42% and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy was related to the degree of kinship of the affected relative, but not to age and gender of the counsellee, nor to the reason for referral or personal history of cancer. Age at diagnosis and multiple primary tumours were reported accurately in 97% and 94% of cases, respectively. In six out of 120 families verification data changed clinical genetic management, in five of these the genetic risk was reduced. Although verification of all reported cancer cases in a family remains the 'gold standard' for clinical as well as research purposes, verification of reports on breast cancer can be limited without seriously compromising medical decision making. In cases where verification is impossible because medical records are unavailable, findings from studies such as ours may help in interpreting family histories.

Family Health↗
PubMed2007

Family system characteristics and psychological adjustment to cancer susceptibility genetic testing: a prospective study.

This study examined prospectively the contribution of family functioning, differentiation to parents, family communication and support from relatives to psychological distress in individuals undergoing genetic susceptibility testing for a known familial pathogenic BRCA1/2 or Hereditary nonpolyposis colorectal cancer-related mutation. Family functioning, differentiation to parents, hereditary cancer-related family communication and perceived support from relatives were assessed in 271 participants for genetic testing before test result disclosure. Hereditary cancer distress (assessed by the Impact of Event Scale) and cancer worry (assessed by the Cancer Worry Scale) were assessed before, 1 week after, and 6 months after test result disclosure. Participants reporting more cancer-related distress over the study period more frequently perceived the communication about hereditary cancer with relatives as inhibited, the nuclear family functioning as disengaged-rigid or enmeshed-chaotic, the support from partner as less than adequate and the relationship to mother as less differentiated. Especially, open communication regarding hereditary cancer and partner support may be important buffers against hereditary cancer distress. Identifying individuals with insufficient sources of support and addressing the family communication concerning hereditary cancer in genetic counseling may help the counselee to adjust better to genetic testing.

Adult↗
PubMed2003

Apolipoprotein B-100 XbaI gene polymorphism in gallbladder cancer.

Genetic polymorphisms in the apolipoprotein B (apoB) gene have been reported to be associated with altered serum lipids and susceptibility to cholesterol gallstones (GS). Gallstones are among the well-known risk factors for carcinoma of the gallbladder (GBC). In the present study, the association between the XbaI polymorphism of the apo B gene was examined in patients with GBC and GS and in normal controls in a north Indian population. DNA samples from patients with GBC (n=153), GS (n=117) and healthy subjects (n=137) were analysed for the apoB- XbaI polymorphism by polymerase chain reaction followed by restriction fragment length polymorphism. The genotype X+/- was less frequent in patients with GBC (39.2%) than in those with GS (68.3%) and in normal subjects (66.4%; P<0.00001). In contrast, there was an increase in the homozygous X-/- genotype in patients with GBC (54.9%) as compared with those with GS (23.9%) and normal subjects (25.5%; P<0.00001). The frequency of the X- allele was found to be significantly increased in GBC patients with or without GS (odds ratio=2.3 and 1.7, respectively). We suggest that the apoB-XbaI gene polymorphism confers susceptibility to carcinoma of the gallbladder under specific environmental conditions.

Adult↗
PubMed2002

High-throughput retroviral tagging to identify components of specific signaling pathways in cancer.

Genetic screens carried out in lower organisms such as yeast, Drosophila melanogaster and Caenorhabditis elegans have revealed many signaling pathways. For example, components of the RAS signaling cascade were identified using a mutant eye phenotype in D. melanogaster as a readout. Screening is usually based on enhancing or suppressing a phenotype by way of a known mutation in a particular signaling pathway. Such in vivo screens have been difficult to carry out in mammals, however, owing to their relatively long generation times and the limited number of animals that can be screened. Here we describe an in vivo mammalian genetic screen used to identify components of pathways contributing to oncogenic transformation. We applied retroviral insertional mutagenesis in Myc transgenic (E mu Myc) mice lacking expression of Pim1 and Pim2 to search for genes that can substitute for Pim1 and Pim2 in lymphomagenesis. We determined the chromosomal positions of 477 retroviral insertion sites (RISs) derived from 38 tumors from E mu Myc Pim1(-/-) Pim2(-/-) mice and 27 tumors from E mu Myc control mice using the Ensembl and Celera annotated mouse genome databases. There were 52 sites occupied by proviruses in more than one tumor. These common insertion sites (CISs) are likely to contain genes contributing to tumorigenesis. Comparison of the RISs in tumors of Pim-null mice with the RISs in tumors of E mu Myc control mice indicated that 10 of the 52 CISs belong to the Pim complementation group. In addition, we found that Pim3 is selectively activated in Pim-null tumor cells, which supports the validity of our approach.

Animals↗
PubMed2005

Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer.

Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normal-derived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/beta-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells.

Animals↗
PubMed2000

Increase of GKLF messenger RNA and protein expression during progression of breast cancer.

Genetic alterations found in carcinomas can alter specific regulatory pathways and provide a selective growth advantage by activation of transforming oncogenes. A subset of these genes, including wild-type alleles of GLI or c-MYC, and activated alleles of RAS or beta-catenin, exhibit transforming activity when expressed in diploid epithelial RK3E cells in vitro. By in vitro transformation of these cells, the zinc finger protein GKLF/KLF-4 was recently identified as a novel oncogene. Although GKLF is normally expressed in superficial, differentiating epithelial cells of the skin, oral mucosa, and gut, expression is consistently up-regulated in dysplastic epithelium and in squamous cell carcinoma of the oral cavity. In the current study, we used in situ hybridization, Northern blot analysis, and immunohistochemistry to detect GKLF at various stages of tumor progression in the breast, prostate, and colon. Overall, expression of GKLF mRNA was detected by in situ hybridization in 21 of 31 cases (68%) of carcinoma of the breast. Low-level expression of GKLF mRNA was observed in morphologically normal (uninvolved) breast epithelium adjacent to tumor cells. Increased expression was observed in neoplastic cells compared with adjacent uninvolved epithelium for 14 of 19 cases examined (74%). Ductal carcinoma in situ exhibited similar expression as invasive carcinoma, suggesting that GKLF is activated prior to invasion through the basement membrane. Expression as determined by Northern blot was increased in most breast tumor cell lines and in immortalized human mammary epithelial cells when these were compared with finite-life span human mammary epithelial cells. Alteration of GKLF expression was confirmed by the use of a novel monoclonal antibody that detected the protein in normal and neoplastic tissues in a distribution consistent with localization of the mRNA. In contrast to most breast tumors, expression of GKLF in tumor cells of colorectal or prostatic carcinomas was reduced or unaltered compared with normal epithelium. The results demonstrate that GKLF expression in epithelial compartments is altered in a tissue-type specific fashion during tumor progression, and suggest that increased expression of GKLF mRNA and protein may contribute to the malignant phenotype of breast tumors.

Animals↗