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At least 523 records · Page 29Linked to original sources
PubMed2003

The APC E1317Q variant in adenomatous polyps and colorectal cancers.

Genetic susceptibility may play a role in many colorectal cancers (CRCs). Known syndromes such as familial adenomatous polyposis and hereditary nonpolyposis CRC account for <5% of CRCs. The germ-line missense variant of the APC gene, E1317Q, has been proposed to confer a risk for colonic adenomatous polyps (adenomas), but not for CRCs in the general population. These findings are contradictory and controversial. In the present study, 608 cases (377 patients with CRC, 145 patients with 4-100 lifetime adenomas, and 86 with < or =3 lifetime adenomas), and 679 controls (362 spouses and 317 patients with normal colonoscopy) were screened for the APC E1317Q variant. The frequency of heterozygotes for E1317Q among patients with CRC (2.4%), patients with 4-100 adenomas (1.4%), and < or =3 adenomas (3.5%) did not differ from spouse controls (2.8%). When CRC patients were examined by DNA mismatch repair status, age at onset (< or =age 50 versus >50), or family history of CRC, no differences in the frequency of E1317Q were found. The APC variant E1317Q does not appear to be associated with increased risk for colorectal neoplasia in the general population. However, when we used normal colonoscopy controls (E1317Q carrier frequency = 0.3%), the prevalence of E1317Q was significantly increased in CRC patients, in patients with < or =3 adenomas, and in CRC patients with intact mismatch repair status, suggesting a possible role for E1317Q in colorectal tumorigenesis. These results underscore the importance of carefully defining the controls to be used in comparisons of allele frequencies.

Adenoma↗
PubMed1994

DNA content of rectal mucosa and rectal mucosal proliferation in individuals at high risk of colorectal cancer.

Genetic changes are important in the development of colorectal cancer. Ploidy and rectal mucosal proliferation were measured in histologically normal rectal mucosa of 85 individuals (mean age 59 years, range 29-74) who had a total colonoscopy. Fifty-one subjects had an adenoma or were undergoing adenoma surveillance. Twenty-two subjects had a strong family history of colorectal cancer and 12 individuals comprised a control group who had a normal colonoscopy without a family history of colorectal cancer. An abnormal DNA content (aneuploidy) was found in the normal mucosa of nine (10.6%) individuals. There was no significant difference in rectal mucosal proliferation with those who had aneuploidy and those who had diploidy. There was a trend towards increased proliferation in those with aneuploidy and adenomas, compared with controls. Of the 35 individuals undergoing adenoma surveillance, eight had recurrent adenomas, and three of these expressed aneuploidy. In the other 27, in whom no adenomas were found, no individual expressed aneuploidy (P = 0.01, Fisher's exact test). Aneuploidy within histologically normal mucosa is an unusual feature, which requires further investigation, particularly in patients developing adenomas.

Adenoma↗
PubMed2000

A putative oncogenic role for MPP11 in head and neck squamous cell cancer.

Genetic alterations of chromosome 7 are common in human cancer. Furthermore, previous studies have supported the presence of a gene important in a broad range of cancers at 7q22-31.1. There is evidence that supports an oncogenic function for this putative gene, as well as evidence that supports a tumor suppressive role. In this study, we used a cross-species candidate gene approach in combination with physical mapping to identify MPP11 as a candidate for the putative cancer-related activity at 7q22-31.1. We then analyzed primary head and neck squamous cell tumors (HNSCCs) for loss of heterozygosity/allelic imbalance (LOH/AI) at the MPP11 genomic locus. Thirty-eight percent of tumors examined displayed LOH/AI involving the MPP11 genomic locus. Mutation analysis of MPP11 in the latter samples did not identify any inactivating mutations. However, immunohistochemical staining of primary tumor sections and Western blot analysis of HNSCC cell lines revealed a tumor-specific high level of expression of MPP11p. Fluorescence in situ hybridization analysis done on the cell lines identified increased chromosome 7 copy number with a concomitant increase in MPP11 copy number. These results suggest an oncogenic role for MPP11 in HNSCC.

Alleles↗
PubMed2006

Natural killer cell-mediated rejection of experimental human lung cancer by genetic overexpression of major histocompatibility complex class I chain-related gene A.

Studies have highlighted molecular and cell biological mechanisms of the NKG2D-NKG2D ligand system in the activation of natural killer (NK) cell and T cell functions. In this study we explore the potential of genetic overexpression of human major histocompatibility complex class I chain-related gene A (MICA), a powerful NKG2D ligand, for the induction of NK cell-mediated antitumor immunity in a humanized murine model of non-small cell lung cancer. Using tissue microarray technology we detected expression of MICA in only 30% of the samples from patients with lung cancer. Staining was always weak and focal, indicating that expression of MICA is detectable but limited in human lung cancer. Genetic overexpression of MICA by means of adenoviral transduction or transfection of expression plasmids was feasible in cell lines in vitro, primary human cancer tissue ex vivo, and in experimental human cancers in vivo. The presence of MICA on the surface of largely NK cell-resistant human lung cancer cells reestablished NK cell susceptibility and provoked NK cell-mediated antitumor immunity by murine and human NK cells in two different experimental therapy models. In this study we analyze the interaction of human NK cells with MICA-positive human cancer cells in an in vivo setting. Our data demonstrate that MICA overexpression can function as NK cell-mediated immunotherapy in experimental lung cancer.

Animals↗
PubMed1998

Hereditary breast cancer.

Genetic predisposition is responsible for 5-10% of all breast cancer, and a much larger percent of early-onset disease. Within the past few years, a number of genes associated with a high risk of breast cancer have been identified, including BRCA1, BRCA2, p53, and the Cowden disease gene PTEN/MMAC1. These genes appear to function as tumor suppressors, and although their mutation frequency in the general population is low, certain populations have a carrier frequency of up to 1% for particular BRCA1 and BRCA2 mutations. The isolation of these genes is likely to provide important insight into the pathogenesis of human cancer. The clinical application of these molecular discoveries raises controversial issues regarding presymptomatic testing for patients suspected of harboring cancer predisposing mutations.

Adult↗
PubMed2006

Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway.

BACKGROUND: Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS: We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS: We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1 gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS: Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.

Aged↗
PubMed2005

Patients' interest in discussing cancer risk and risk management with primary care physicians.

Little is known about patients' preferences for discussing cancer risks and risk management with primary care physicians. We sought to determine whether patients want to discuss such topics and what factors are associated with this interest. Participants (375 patients ages 40-85, of diverse race and education level) completed a telephone survey prior to scheduled physician visits. Survey included items on perceived health, perceived cancer risk, education level, and whether participants would like to discuss with a physician their breast, ovarian or colon cancer risk, tamoxifen, cancer genetic counseling, and colon cancer screening. Greater proportions were interested in discussing risks for each cancer, compared with those who were not (P < 0.0001). More participants were interested in discussing mammograms (80%) and cancer genetic counseling (60%) than tamoxifen (49%) or colon cancer screening modalities (43-53%). For many topics, poorer perceived health was associated with greater interest in future discussion; higher education level was associated with less interest.

Adult↗
PubMed2005

CGMIM: automated text-mining of Online Mendelian Inheritance in Man (OMIM) to identify genetically-associated cancers and candidate genes.

BACKGROUND: Online Mendelian Inheritance in Man (OMIM) is a computerized database of information about genes and heritable traits in human populations, based on information reported in the scientific literature. Our objective was to establish an automated text-mining system for OMIM that will identify genetically-related cancers and cancer-related genes. We developed the computer program CGMIM to search for entries in OMIM that are related to one or more cancer types. We performed manual searches of OMIM to verify the program results. RESULTS: In the OMIM database on September 30, 2004, CGMIM identified 1943 genes related to cancer. BRCA2 (OMIM *164757), BRAF (OMIM *164757) and CDKN2A (OMIM *600160) were each related to 14 types of cancer. There were 45 genes related to cancer of the esophagus, 121 genes related to cancer of the stomach, and 21 genes related to both. Analysis of CGMIM results indicate that fewer than three gene entries in OMIM should mention both, and the more than seven-fold discrepancy suggests cancers of the esophagus and stomach are more genetically related than current literature suggests. CONCLUSION: CGMIM identifies genetically-related cancers and cancer-related genes. In several ways, cancers with shared genetic etiology are anticipated to lead to further etiologic hypotheses and advances regarding environmental agents. CGMIM results are posted monthly and the source code can be obtained free of charge from the BC Cancer Research Centre website http://www.bccrc.ca/ccr/CGMIM

Algorithms↗
PubMed2002

Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer.

Genetic changes involved in the development and progression of pancreatic cancer are still partly unknown, despite the progress in recent years. In this study, comparative genomic hybridization analysis in 31 pancreatic cancer cell lines showed that chromosome arms 8q, 11q, 17q, and 20q are frequently gained in this tumor type. Copy number analysis of selected genes from these chromosome arms by fluorescence in situ hybridization showed amplification of the MYC oncogene in 54% of the cell lines, whereas CCND1 was amplified in 28%. In the 17q arm, the ERBB2 oncogene was amplified in 20% of the cell lines, TBX2 in 50%, and BIRC5 in 58%, indicating increased involvement toward the q telomere of chromosome 17. In the 20q arm, the amplification frequencies varied from 32% to 83%, with the CTSZ gene at 20q13 being most frequently affected. These results illustrate that amplification of genes from the 8q, 11q, 17q, and 20q chromosome arms is common in pancreatic cancer.

Chromosomes, Human↗
PubMed2002

Impact of DNA amplification on gene expression patterns in breast cancer.

Genetic changes underlie tumor progression and may lead to cancer-specific expression of critical genes. Over 1100 publications have described the use of comparative genomic hybridization (CGH) to analyze the pattern of copy number alterations in cancer, but very few of the genes affected are known. Here, we performed high-resolution CGH analysis on cDNA microarrays in breast cancer and directly compared copy number and mRNA expression levels of 13,824 genes to quantitate the impact of genomic changes on gene expression. We identified and mapped the boundaries of 24 independent amplicons, ranging in size from 0.2 to 12 Mb. Throughout the genome, both high- and low-level copy number changes had a substantial impact on gene expression, with 44% of the highly amplified genes showing overexpression and 10.5% of the highly overexpressed genes being amplified. Statistical analysis with random permutation tests identified 270 genes whose expression levels across 14 samples were systematically attributable to gene amplification. These included most previously described amplified genes in breast cancer and many novel targets for genomic alterations, including the HOXB7 gene, the presence of which in a novel amplicon at 17q21.3 was validated in 10.2% of primary breast cancers and associated with poor patient prognosis. In conclusion, CGH on cDNA microarrays revealed hundreds of novel genes whose overexpression is attributable to gene amplification. These genes may provide insights to the clonal evolution and progression of breast cancer and highlight promising therapeutic targets.

Breast Neoplasms↗
PubMed1987

Strategies to control cancer through genetics.

Although genetic factors may be essential in only a fraction of common cancers, it is important to identify individuals who merit genetic evaluation. The occurrence of cancer in an individual under one of the following circumstances may indicate an increased susceptibility to malignancy as a result of predisposing factors: cancer in both of paired organs, thought not to be the result of metastasis; more than one focus of cancer in a single organ (multifocal tumors); histologically similar malignant neoplasms in different parts of the same organ system; two histologically distinct cancers (multiple primary malignancies); cancer at an atypical age; at an atypical site; in the usually less often affected sex; associated with birth defects; associated with precursor lesions; in a person with immunodeficiency; or in a patient with one of the 200 Mendelian disorders where cancer is part of the clinical picture or a frequent complication. At risk are first-degree relatives of people who meet any of the above criteria. Also, a person should be considered at risk if two first-degree relatives had any form of cancer. A strategy to control cancers utilizing genetic knowledge should include such measures as: genetic counseling of individuals at risk for specific cancers because of a congenital or genetic disease in themselves or their relatives, or because of the pattern of cancer occurrence in the family; prenatal diagnosis for families with genetic conditions that predispose to cancer and are amenable to prenatal testing; surveillance of high-risk individuals to detect early manifestations of new or recurrent disease; prophylactic removal of the target organ or tissue in appropriate cases; limiting exposure of high-risk individuals to known carcinogens or supplementing diets of high-risk individuals with anticarcinogens; and educational and administrative measures to promote practical application of genetic knowledge and to increase awareness of genetic factors in the etiology of cancer. Far from all individuals who are exposed to carcinogenic factors contract cancer, and in another common disease, atherosclerosis, it is well known that there is genetically determined variation in response to environmental or lifestyle factors that can cause disease. The emerging fields of human ecogenetics and predictive testing together with research progress in medical and molecular genetics are likely to improve greatly the possibilities for utilizing genetic knowledge to control cancer.

Environment↗
PubMed1973

Etiology of breast cancer. I. Genetic aspects.

The subject of breast cancer is reviewed with particular emphasis on the genetic aspect of its etiology. A number of studies using various approaches gave the same results: the familial form occurs earlier and there is a higher risk in female members of the breast-cancer families. An association between breast cancer and cancer of certain other sites among women is reported. Cytogenetic studies of "cancer families" revealed increased frequency of aneuploidy in some members. However, the role of chromosome abnormalities in carcinogenesis is still not clear.

Adenocarcinoma↗
PubMed1996

[Genetic counseling for families at high cancer risk].

About 5-10% of the most common cancers, such as breast, colon and melanoma, result from mutations in inherited predisposition genes. Recently some of these genes have been mapped or even cloned. These advances in cancer genetics have made more precise genetic counseling possible for cancer patients and their families. In our clinic for specific genetic counseling 180 families with a history of cancer were seen during a 10-month period. In counseling sessions, the family history was confirmed and interpreted, personal risk was estimated and the availability of molecular genetic testing was presented. Blood samples for DNA testing were drawn from those with certain criteria who wished to be tested. Instructions for early detection were also given, depending on the personal risk of cancer as compared to that of the general population.

DNA↗
PubMed2000

Metabolizing enzyme genotype and risk for upper aerodigestive tract cancer.

Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of upper aerodigestive tract cancer. It has been suggested that such polymorphisms may be linked to cancer susceptibility. Using a case-control molecular epidemiologic approach, the association between many of these genetic polymorphisms and susceptibility to upper aerodigestive tract cancer has been investigated in numerous studies. In this review, we summarize the findings of these studies, analyzing potential associations with upper aerodigestive tract cancer risk in terms of gene:environment interactions, genotype-induced functional defects in enzyme activity and/or expression, and the influence of race on these associations.

Carcinogens↗
PubMed2006

CpG island methylation of genes accumulates during the adenoma progression step of the multistep pathogenesis of colorectal cancer.

Genetic alterations occur during the adenoma-carcinoma sequence of colon cancer formation and drive the initiation and progression of colon cancer formation. The aberrant methylation of genes is an alternate, epigenetic mechanism for silencing tumor suppressor genes in colon cancer. The aim of this study was to determine on a global and gene-specific level the role of CpG island methylation in the initiation and progression of colon cancer. Consequently, we assessed the frequency of gene methylation in tumors representative of the commonly recognized histological steps of the adenoma-carcinoma progression sequence through the analysis of eight genes previously identified to be methylated in colon cancer, MGMT, HLTF, MLH1, p14(ARF), CDKN2A, TIMP3, THBS1, and CDH1. We observed that the proportion of tumors carrying methylated alleles increased from adenomas to adenocarcinomas but that the proportion of tumors with methylated alleles was not different between adenocarcinomas and metastases (69% versus 90%, P = 0.01 and 90% versus 81%, P > 0.05). The most substantial difference occurred between early and advanced adenomas (47% versus 84%, P = 0.018). Furthermore, we observed that the frequency of gene methylation at the different steps of the progression sequence varied between genes. Thus, the aberrant methylation of genes appears to increase most significantly during the progression of early adenomas to advanced adenomas, and the frequency of specific gene methylation at the different steps of the adenoma-carcinoma progression sequence varies in a gene-specific fashion.

Adenocarcinoma↗
PubMed2006

Beliefs and interest in cancer risk in an underserved Latino cohort.

OBJECTIVE: To measure beliefs about cancer causation, cancer screening behaviors, access to information about and resources for cancer screening, and interest in cancer genetics services in two underserved predominantly Latino communities. METHODS: An anonymous survey, in both English and Spanish, was distributed at the registration desk to all attendees of selected general medicine clinics in two underserved healthcare systems. RESULTS: There were a total of 312 respondents, representing 98% of eligible candidates. The reported data focus on 75.3% (n=235) of Latino respondents; mean age 43 years; 78% female; 72% less than high school education. Heredity was perceived as the most frequent cause of cancer, after smoking. Only 37% knew of free cancer screening programs. Over 85% expressed interest in obtaining information about personal cancer risk and motivation to participate in cancer genetics services. CONCLUSIONS: The results of this survey demonstrate an awareness of heredity as a potential cause of cancer. The observed high level of interest in cancer genetics services suggests the acceptability of cancer genetics services in this predominantly underserved Latino population. Furthermore, cancer genetics services would likely augment awareness and utilization of available cancer screening services in the community.

Adolescent↗
PubMed1992

Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer.

Genetic alterations are believed to be important in the origin and dissemination of breast cancer. Cytogenetic rearrangements on chromosome 7 are common in breast tumours. We used the c-met proto-oncogene probe, which detects sequences on chromosome 7q31, to analyse tumour and blood leucocyte DNA samples from 245 patients with primary breast cancers. The pmetH polymorphic probe detected a high frequency of allele loss (40.5%) among the 121 informative (heterozygous) patients. This genetic alteration was not significantly associated with standard prognostic features including tumour size, histopathological grade, and lymph-node or steroid receptor status. However, patients with loss of heterozygosity on chromosome 7q31 in primary tumour DNA had significantly shorter metastasis-free survival (p = 0.00022) and overall survival (p = 0.0036) after surgery than patients without this alteration. These findings indicate that this region of chromosome 7 might be the site of a breast tumour or metastasis suppressor gene.

Alleles↗