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PubMed2025

Gene and pathway analysis of genome-wide genetic associations of bladder cancer.

BACKGROUND: Although genetic variants associated with bladder cancer (BCa) risk have been identified through hypothesis-driven and genome-wide association studies, a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved. MATERIALS AND METHODS: In this 2-stage functional genomics study, we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics, followed by a meta-analysis of gene-level significance p values, to obtain a consensus gene ranking in terms of association with BCa. Subsequently, we performed preranked gene-set enrichment analysis to identify the functional pathways involved in BCa genetic susceptibility. Joint analysis with gene-set enrichment analysis, based on somatic alteration frequency, was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa. RESULTS: Other than the well-known BCa genes (such as FGFR3, MYC, TERT, CCNE1, and TP63), we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development, including SETD2, a possible tumor suppressor gene involved in chromatin remodeling. We further demonstrated convergence between genetic associations and somatic alterations at both the gene (eg, FGFR3 and TERT) and pathway levels (eg, cell cycle and chromatin modification), as well as functional ontologies specifically implicated in germline predisposition to BCa (eg, CD8/TCR signaling, immune checkpoints, and cytokine signaling). CONCLUSIONS: We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the development of BCa by affecting antitumor immunity, response to toxic exposure, and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.

Bladder cancer↗
PubMed2005

Modern cancer epidemiological research: genetic polymorphisms and environment.

Individual cancer susceptibility seems to be related to factors such as changes in oncogenes and tumor suppressor genes expression, and differences in the action of metabolic enzymes and DNA repair regulated by specific genes. Epidemiological studies on genetic polymorphisms of human xenobiotics metabolizing enzymes and cancer have revealed low relative risks. Research considering genetic polymorphisms prevalence jointly with environmental exposures could be relevant for a better understanding of cancer etiology and the mechanisms of carcinogenesis and also for new insights on cancer prognosis. This study reviews the approaches of molecular epidemiology in cancer research, stressing case-control and cohort designs involving genetic polymorphisms, and factors that could introduce bias and confounding in these studies. Similarly to classical epidemiological research, genetic polymorphisms requires considering aspects of precision and accuracy in the study design.

Carcinogens, Environmental↗
PubMed2002

Clinical interpretation and recommendations for patients with a variant of uncertain significance in BRCA1 or BRCA2: a survey of genetic counseling practice.

The intent of this study was to document current practices in breast cancer genetic counseling and identify areas of variability for patients with a variant of uncertain significance (VUS) in the BRCA1 or BRCA2 gene. Registered members of the National Society of Genetic Counselors (NSGC) Cancer Special Interest Group (SIG) were sent an invitation via electronic mail to participate in an online questionnaire. The questionnaire was divided into three sections: clinical experience, clinical meaning, and risk perceptions and clinical recommendations for clinical situations involving a VUS. Fifty-seven of the eligible members responded. During the pre-test counseling session for a BRCA risk assessment patient, the vast majority of counselors (80.7%) mention VUS as a possible test result. Nearly half, 49.1%, report having given such a result to their patients at least one to four times. However, only 63.2% felt as though their patients understood the meaning of a VUS result. When asked to conclude the implication of a VUS and make medical management recommendations, the responses were varied. Nevertheless, a good proportion of counselors expressed the importance of testing other family members to help clarify the proband's risk and aid in medical management issues. Although the recent recommendations by the American College of Medical Genetics suggest standards for the interpretation of sequence variations, they do not provide guidelines for making clinical recommendations based on these variations. The results of this study reveal significant diversity in the personal interpretation of a VUS result, leading to various clinical recommendations, and suggest a need for clinical management recommendations as well.

Female↗
PubMed1994

Recent developments in the molecular genetic understanding of breast cancer.

The molecular genetic characterization of breast cancer has implicated or identified the involvement of at least 10 distinct gene alterations in the genesis or progression of this disease. The genes involved fall into three distinct classes, possibly reflecting their particular function in the tumorigenic process. First, there is a class of genes that is being amplified to various levels in clinically manifest breast cancer, most conspicuously c-neu, c-myc, and cyclin D1. Second, an as-yet unknown number of genes are targets for loss of heterozygosity or allelic imbalance events on a number of different chromosomes. Presumably, this reflects the presence of tumor suppressor genes located on chromosomes 3p, 6q, 16q, 17, and possibly a few additional chromosomes. Finally, at least three genes are implicated to confer heritable predisposition to breast cancer. These include the p53 oncogene on 17p, an as yet unknown gene on 17q, and at least one locus outside these regions. While a number of presently unknown genes will soon be identified and cloned, it is becoming evident from genetic mapping studies that the complexity of gene involvement in breast cancer has not yet seen its very limits. A comprehensive multidisciplinary molecular profiling of a large series of tumors of various histological subtypes may aid in understanding how the different genes may cooperate to cause breast cancer.

Breast Neoplasms↗
PubMed1977

Genetic markers and cancer epidemiology.

The study of potential associations between genetic markers and various cancers has a long history in cancer epidemiology. Such investigations are subject to serious problems of statistical significance and the choice of appropriate control populations. A promising future for the use of human population genetics in cancer epidemiology may be in the investigation of genetic markers (such as the HL-A complex) which code for proteins of potential immunological or physiological importance in susceptibility or resistance to cancer. The cerumen gentic marker has played a central part in a hypothesis formulated in our laboratory for the etiology of breast cancer. A second new development in this field is likely to be the investigation of genetic markers in families with high incidence of cancer. Such families permit the simultaneous study of genetic hypotheses of cancer inheritance and the association of marker genotypes with cancer through segregation and linkage analysis.

ABO Blood-Group System↗
PubMed1996

Ethical and scientific considerations for chemoprevention research in cohorts at genetic risk for breast cancer.

Identification of cohorts at genetic risk for cancer offers unique research opportunities to explore the steps in carcinogenesis, from the inheritance of a predisposing mutation to the development of preinvasive lesions or overt malignancy, and to evaluate interventions to modulate the carcinogenic process. However, cancer prevention strategies for most inherited cancer predisposition syndromes are of unproven benefit, and the potential for adverse psychosocial effects and employment or insurance discrimination associated with genetic testing is substantial. Thus testing for genetic cancer risk remains highly controversial, and the National Center for Human Genome Research and the American Society of Human Genetics advise DNA testing for presymptomatic identification of cancer risk only in the setting of a carefully monitored research environment. The commercial availability of predictive genetic testing, particularly for inherited susceptibility to cancer, has focused attention not only on the urgent need for research in cancer prevention for cohorts at genetic cancer risk but also on ethical considerations surrounding clinical prevention research in genetic risk groups. This paper addresses the interrelationship of ethical and scientific issues in conducting chemoprevention research in these cohorts, especially for those studies which require presymptomatic testing for specific gene mutations as a study entry criterion or as a criterion for stratification. Practical approaches to study design and implementation issues for chemoprevention research in genetic risk cohorts are discussed, emphasizing the interactions of ethical and scientific considerations at all levels of the research process.

Anticarcinogenic Agents↗
PubMed2000

Men's attitudes regarding genetic testing for hereditary prostate cancer risk.

OBJECTIVES: Little is known about the attitudes of men unselected for a family history for prostate cancer concerning genetic testing for prostate cancer risk or genetic testing for inherited cancer predisposition. To explore this, we examined the interest in molecular testing for hereditary prostate cancer (HPC) predisposition among a self-selected cohort of 342 men presenting for prostate cancer screening. METHODS: Participants were surveyed concerning their attitudes about DNA testing for HPC predisposition and knowledge of prostate cancer-associated risk factors, including heredity. RESULTS: Of the participants completing the survey, 92% expressed interest in learning about DNA testing, and 89% stated that they would undergo DNA analysis for HPC predisposition, if available. Twenty-eight percent of respondents failed to demonstrate an adequate understanding of the concept of "inherited tendency." The demonstrated level of understanding of this concept did not differ by the respondent's family history, although it varied by race. An interest in learning about or undergoing testing did not vary by race, family history, or demonstrated understanding of the concept of inherited risk. CONCLUSIONS: Among men presenting for routine prostate cancer screening, interest in learning about testing for HPC predisposition and in having such testing performed may be high. The data also provide evidence that, in a population of men unselected for family history, interest in molecular testing for this common, male-specific cancer may parallel the high interest level demonstrated among women in DNA testing for inherited breast and ovarian cancer risk.

Adult↗
PubMed1996

Attitudes of 47 mothers of pediatric oncology patients toward genetic testing for cancer predisposition.

PURPOSE: To assess attitudes toward testing for cancer susceptibility genes, we interviewed mothers of pediatric oncology patients about their cancer causation theories, interest in hypothetical predisposition testing for themselves and their healthy children, and anticipated impact of testing. PATIENTS AND METHODS: The subjects were 47 mothers of two or more living children, one of whom was 6 to 24 months postdiagnosis of cancer. Potential risks and benefits of hypothetical genetic predisposition testing for cancer susceptibility were described. A semistructured interview assessed the following: (1) recall of discussions with the pediatric oncologist about the possible role of heredity in causing the child's cancer; (2) mothers' personal theories of the etiology of their child's cancer; (3) family cancer history; (4) interest in genetic predisposition testing for themselves and unaffected (cancer-free) children; and (5) expected sequelae of testing. RESULTS: If genetic cancer predisposition tests were available, 51% of mothers would test themselves and 42% would test healthy children, even with no medical benefit. With established medical benefit, an additional 36% of mothers would seek testing for themselves and another 49% would test their healthy children. Interest in cancer predisposition testing among mothers extended far beyond those with significant family histories of cancer. Most mothers would consider minor children's wishes in the decision about testing and would tell children under age 18 their test results. CONCLUSION: As increasing numbers of cancer susceptibility genes are identified, parents of pediatric oncology patients may be receptive to opportunities to test themselves and their healthy children. Counseling will be important to aid in decisions about testing. Research is essential to evaluate the long-term impact of predisposition testing.

Attitude↗
PubMed2006

BRCA1 and BRCA2 mutations in breast and ovarian cancer syndrome: reflection on the Creighton University historical series of high risk families.

Over the last four decades, Henry Lynch has collected pedigrees and samples from high risk breast and/or ovarian cancer families, generating a unique resource for the study of breast cancer susceptibility. These families have made a major contribution to increasing our knowledge in the cancer genetic susceptibility field, allowing the discovery of a genetic association between breast and ovarian cancer predisposition, contributing to the mapping of the BRCA1 and BRCA2 genes, advancing the idea of the existence of other breast cancer susceptibility genes, allowing the evaluation of BRCA-associated cancer risks and psychosocial aspects of BRCA testing and so on. Ten years after the cloning of BRCA1 and BRCA2, we report the current status of these families and compare the observed BRCA1/2 mutation detection rate with the estimations obtained by linkage analysis of the Breast Cancer Linkage Consortium families.

BRCA1 Protein↗
PubMed1997

Investigation and management of patients at high risk of developing cancer.

Recent developments in cancer genetics have revealed genes that render individuals susceptible to cancer. These families have a unique set of new problems and benefits that must be thought through for the potential good to be accrued from these discoveries. Individual patients seek early diagnosis and prevention strategies that challenge the limits of current knowledge. Some available methods have not yet been evaluated. There is a need for the evidence to support plans of care, and consistency is required from one centre to the next in the advice given. These familial cancers are often different from the more common sporadic cases, and so traditional treatments need to be tested again in the context of the new genetic knowledge. Three groups of cancers, breast, ovary and colon, have been used to illustrate the issues surrounding these high risk families, their investigation and care. In applying new strategies to these patients, ethical issues arise that are new to the medical world, and must be considered by the lay public. It is up to the medical profession, patients and society to use this knowledge to give benefit to a vulnerable group, and not to give unaffordable hopes and unnecessary anxieties.

Adult↗
PubMed2004

Identifying multiple changepoints in heterogeneous binary data with an application to molecular genetics.

Identifying changepoints is an important problem in molecular genetics. Our motivating example is from cancer genetics where interest focuses on identifying areas of a chromosome with an increased likelihood of a tumor suppressor gene. Loss of heterozygosity (LOH) is a binary measure of allelic loss in which abrupt changes in LOH frequency along the chromosome may identify boundaries indicative of a region containing a tumor suppressor gene. Our interest was on testing for the presence of multiple changepoints in order to identify regions of increased LOH frequency. A complicating factor is the substantial heterogeneity in LOH frequency across patients, where some patients have a very high LOH frequency while others have a low frequency. We develop a procedure for identifying multiple changepoints in heterogeneous binary data. We propose both approximate and full maximum-likelihood approaches and compare these two approaches with a naive approach in which we ignore the heterogeneity in the binary data. The methodology is used to estimate the pattern in LOH frequency on chromosome 13 in esophageal cancer patients and to isolate an area of inflated LOH frequency on chromosome 13 which may contain a tumor suppressor gene. Using simulations, we show that our approach works well and that it is robust to departures from some key modeling assumptions.

Chromosomes, Human, Pair 13↗
PubMed2003

The importance of paternal family history in hereditary breast cancer is underappreciated by health care professionals.

OBJECTIVES: Cancer genetics clinics have been established in many major oncology centers worldwide in recent years. For such specialized clinics to fulfill their function, primary care physicians need to identify high-risk patients for referral. METHODS: We conducted a survey to evaluate the level of awareness of breast cancer risk factors and hereditary breast cancer among health care providers and patients. RESULTS: 284 health care professionals, 221 medical students, 104 breast cancer patients and 177 cancer-free women participated in the study. Less than half of the patients with breast cancer were aware of their risk for another breast cancer or of the increased breast cancer risk of their sisters and daughters. Less than one quarter of the health care professionals and medical students knew the importance of paternal family history in the evaluation for hereditary breast cancer. Only about half of the health care professionals and medical students and less than one third of the breast cancer patients and cancer-free women knew about genetic testing and prophylactic mastectomy as options for women at risk for hereditary breast cancer. CONCLUSIONS: Health care providers and medical students lack basic genetic knowledge and are not aware of emerging diagnostic and preventive options for hereditary breast cancer. Inclusion of cancer genetics in the continuing medical education of health care providers is important to promote such awareness.

Adult↗
PubMed2004

Unravelling the genetics of prostate cancer.

This review describes what is currently known about the genetics of prostate cancer. Traditionally, the genetics of a suspected inherited cancer predisposition have generally been thought of in terms of a single, high-risk gene with a dominant mode of inheritance. Such a gene might be observed in families, as has been documented in familial breast cancer (BRCA1/2), familial colorectal cancer (HNPCC), retinoblastoma (RB1), and Wilms tumor (WT1). This review investigates the evidence for the existence, first of familial prostate cancer, and second, for the presence of such a high-risk gene in those families by epidemiological and experimental approaches. Another current area of interest in prostate cancer is the investigation of the contribution of common lower penetrance genes to the disease. This alternative approach has become popular, as it raises the issue of frequently seen genetic variations such as single nucleotide polymorphisms (SNPs) having relevance to the risk of developing the disease. Finally, this article will explore the way forward, with emphasis on worldwide collaboration from teams attempting to find the genes responsible for the disease and investment in new technologies that will aid in their discovery.

Genetic Predisposition to Disease↗
PubMed1999

Relationships among breast cancer concern, risk perceptions, and interest in genetic testing for breast cancer susceptibility among African-American women with and without a family history of breast cancer.

There has been very little research exploring the relationships among perceptions of, and concern about, getting breast cancer and interest in genetic testing for breast cancer among African-American women with and without a family history of breast cancer. This study explored these issues among 130 and 136 African-American women with and without a family history of breast cancer, respectively. Women with a family history reported having greater perceived breast cancer risks and concerns than women without a family history of breast cancer. Knowledge of breast cancer risk factors was very poor and correlated weakly with perceptions of risk and concern. In attributional analyses, acknowledging one's family history status was the strongest predictor of perceived risk only among women with a family history. Women with a family history of breast cancer expressed greater interest in genetic testing for breast cancer susceptibility than women without a family history, although interest in testing was high overall. Increasing perceptions of breast cancer risks and concerns were related to a greater interest in genetic testing, and this relationship was not moderated by family history status. Attributions of risk and knowledge of breast cancer risk factors generally were not related to interest in testing. Overall, these results suggest that: (a) African-American women with a family history are more concerned about and do recognize their greater risk of breast cancer; (b) knowledge of risk factors and attributions of risk are not directly related to interest in genetic testing; and (c) concerns, rather than beliefs about one's risk, are more powerfully related to interest in genetic testing, independent of family history status.

Adult↗
PubMed1981

Sex differences in lung cancer incidence: a genetic model.

Family histories pertaining to cancer of all anatomic sites were ascertained on 88 Caucasian patients (61 males, 27 females) with histologically verified lung cancer. Lifetable analysis revealed that relatives of female probands had a significantly higher risk for cancer (all sites) at younger age (p less than .04) compared to relatives of male probands. This trend was peculiar to nonsmoking-associated cancer sites, and was not apparent for smoking-associated cancer sites. We hypothesize that certain components of genetic liability to lung cancer are common to nonsmoking-associated malignant neoplasms, and that females who develop lung cancer are more extreme with respect to genotype than are males who develop lung cancer. Our hypothesis accounts for the lower incidence of lung cancer among females, as well as the apparent increased susceptibility to cancer among their relatives.

Adult↗
PubMed2004

Active recruitment increased enrollment in a hereditary cancer registry.

BACKGROUND AND OBJECTIVE: The Mid-Atlantic Cancer Genetics Network (MACGN) targets individuals from cancer risk assessment clinics for recruitment into a national hereditary cancer registry. We sought to determine whether different recruitment methods used in a high-risk breast and ovarian cancer clinic yielded differences into enrollment into MACGN. METHODS: Two methods of recruitment were compared over an 8-month period. A passive recruitment technique, used during the first 4 months of recruitment, involved distribution of a brochure. An active recruitment method, used during the second 4-month period, required a MACGN recruiter to approach patients and initiate a brief discussion of the registry. RESULTS: During the first 4-month period, 158 eight patients were seen in the clinic and 142 were seen in the second 4-month period. During passive recruitment, 20% of available patients were approached, compared with 63% during active recruitment. Active recruitment also resulted in fourfold increase over passive recruitment in enrollment (from 15.6% to 67.4%). CONCLUSION: Allocating research staff specifically for recruitment and personal contact with potential participants is effective in achieving increased enrollment into a national hereditary cancer research registry.

Adult↗
PubMed2005

Nature and nurture - lessons from chemical carcinogenesis.

The roles of genetic constitution versus environmental factors in cancer development have been a matter of debate even long before the discovery of 'oncogenes'. Evidence from epidemiological, occupational and migration studies has consistently pointed to environmental factors as the major contributing factors to cancer, so it seems reasonable to discuss the importance of chemical carcinogenesis in the present 'age of cancer genetics'.

Animals↗
PubMed2003

Genomic microarrays in human genetic disease and cancer.

Alterations in the genome that lead to changes in DNA sequence copy number are a characteristic of solid tumors and are found in association with developmental abnormalities and/or mental retardation. Comparative genomic hybridization (CGH) can be used to detect and map these changes. Recent improvements in the resolution and sensitivity of CGH have been possible through implementation of microarray-based CGH (array CGH). Here we discuss the performance characteristics of different array platforms and review some of the recent applications of array CGH in cancer and medical genetics.

Genetic Diseases, Inborn↗