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At least 613 records · Page 34Linked to original sources
PubMed2002

Early onset prostate cancer: predictors of clinical grade.

PURPOSE: Prostate cancer is typically a disease of elderly men and, therefore, it has not been well characterized in those affected at a young age. With the advent of serum prostate specific antigen testing, we are able to detect prostate cancer in young men even in the absence of symptoms. We studied a large group of early onset prostate cancer cases to illustrate the clinical presentation of men with early onset prostate cancer and to determine the effect of family history on Gleason grade as a reflection of prognosis. MATERIALS AND METHODS: All study participants were enrolled in the University of Michigan Prostate Cancer Genetics Project. Enrollment criterion of the Prostate Cancer Genetics Project includes a diagnosis of prostate cancer at age 55 years or younger. Descriptive statistics and logistic regression were used to characterize early onset prostate cancer and assess the associated prognostic factors. RESULTS: The study group was comprised of 257 men with prostate cancer diagnosed at age 55 years or younger. Median age at diagnosis was 51 years (range 34 to 55) and almost half of the participants reported a negative family history of prostate cancer. In logistic regression analysis having an affected father, an affected first-degree relative or an affected relative of any relation was each a statistically significant predictor of well differentiated (Gleason 6 or less) compared to moderately and poorly differentiated prostate cancer (Gleason 7-10) after adjusting for confounding variables. Men with an affected relative were nearly twice as likely to have well differentiated prostate cancer compared to men without affected relatives. CONCLUSIONS: Family history appears to predict the development of well differentiated tumors independently. In our study men with no family history of prostate cancer had higher grade tumors, which are associated with a more serious prognosis. Future studies of early onset prostate cancer should be directed toward identifying additional risk factors that may be relevant for men without a family history of the disease.

Adult↗
PubMed1996

[Effect of hereditary factors on tolerance for surgical treatment in patients with lung cancer].

Genetic polymorphism at 10 independent loci (ABO, RH, HP, GC, PI, TF, ACP1, PGM1, GLO1, and PTC) was studied in male patients with lung squamous cell carcinoma. These patients were divided into two groups, depending on their tolerance for surgical intervention and on the postoperative course: (1) patients with an uneventful postoperative period and (2) patients with postoperative complications. The genetic structure of the combined sample at the loci studied did not differ from that of the control group consisting of health people (population control). Genotypic differences might manifest at the postoperative stage rather than at the onset of the disease, and determine the presence of postoperative complications. However, comparative analysis of the two groups of patients revealed their polar divergence in respect to phenotype and gene frequencies at certain loci. Moreover, the genotypic structure of patients in both groups differed from that in the combined sample and in the population control. In the group with postoperative complications, higher frequencies of the alleles GC*1F, ACP1*A, and HP*2 were observed. By contrast, the group of patients with an uneventful postoperative period demonstrated prevalence of the alternative alleles of these loci: GC*2, ACP1*B, and HP*1. The greatest difference in the distribution of informative allele frequencies was observed between the group of patients with postoperative complications and the control group. This is evidence that these groups significantly differ in their genetic structure. Such divergence is largely determined by the polymorphic multifunctional systems of serum proteins.

Adult↗
PubMed2004

Truncating BRCA1 mutations are uncommon in a cohort of hereditary prostate cancer families with evidence of linkage to 17q markers.

PURPOSE: A genome-wide scan of 175 hereditary prostate cancer families from the University of Michigan Prostate Cancer Genetics Project provided evidence of prostate cancer linkage to 17q markers near the BRCA1 gene. To examine the possibility that germ-line BRCA1 mutations were associated with hereditary prostate cancer, individuals from 93 families with evidence of linkage to chromosome 17q were screened for germ-line BRCA1 mutations. EXPERIMENTAL DESIGN: One individual from each of the 93 families, the majority with three or more cases of prostate cancer, were screened for BRCA1 mutations with denaturing high-performance liquid chromatography (HPLC). Fragments exhibiting denaturing HPLC variant patterns were additionally analyzed by direct sequencing. RESULTS: Sixty-five of the individuals selected for sequencing from 65 unrelated families were determined to have wild-type BRCA1 sequence by denaturing HPLC. One individual from a family with both prostate and ovarian cancer was found to have a truncating BRCA1 mutation (3829delT). An additional 27 germ-line variants were identified, including 15 missense variants. CONCLUSIONS: These sequencing results suggest that BRCA1 truncating mutations do not account for the linkage evidence on chromosome 17 observed in University of Michigan Prostate Cancer Genetics Project families. A recently completed combined genome scan has also detected linkage to 17q22, and studies are ongoing to identify the relevant prostate cancer susceptibility gene in this region.

Animals↗
PubMed1997

Hereditary ovarian cancer: molecular genetics and clinical implications.

Epidemiologic data support the existence of two discrete manifestations of hereditary ovarian carcinoma: the breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Genetic linkage analyses reveal that the majority of breast and ovarian cancer families are linked to the BRCA1 gene, while some cases of hereditary ovarian cancer are also apparent in breast cancer families linked to the BRCA2 gene. The majority of HNPCC families are linked to one of four genes encoding a family of DNA mismatch repair proteins. Molecular analyses demonstrate that genetic screening for germline transmission of a defective allele of one or another of these genes is now possible for high-risk individuals. The ethical, legal, and social implications of this type of analysis are multiple and complex, and genetic counseling requires a thorough understanding of these issues and a cautious approach to most effectively meet the special needs of this patient population. Increased medical surveillance and prophylactic oophorectomy are among the management options that may be appropriate for some genetically predisposed, asymptomatic women. Further research is needed regarding the most effective use of this genetic information in formulating counseling and clinical management strategies.

BRCA2 Protein↗
PubMed2004

Microsatellite markers in breast cancer studies.

Microsatellites are tandem repeats of simple polymorphic sequences randomly distributed in non-coding regions of DNA. They can be used in cancer genetics and indirect cancer diagnosis and can help unraveling the genetic basis of tumor formation and progression of cancer. Breast cancer is a complex disease in which numerous genetic alterations occur. The knowledge of specific genetic changes and their biological consequences is critical to an understanding of breast cancer tumorigenesis, screening and treatment of patients. Microsatellites can undergo two events during tumor progression. Loss of heterozygosity indicates absence of one allele in a given locus, which is associated with the loss of a corresponding genes. Microsatellite instability reflects replication errors induced by defective function of mismatch repair genes and is demonstrated with the appearance of novel, noninherited alleles in tumor cells and represents a specific pathway of tumor development. Both events serve as prognostic markers, which can be correlated with clinicopathological features and can help exploring breast cancer formation.

Breast Neoplasms↗
PubMed1999

Genetic pattern of prostate cancer progression.

Genetic alterations in primary prostate cancer (CaP) have been extensively studied, yet little is known about the genetic mechanisms underlying progression of primary CaP to metastatic prostate cancer. As a result, it is not possible to distinguish clinically indolent localized disease from potentially life-threatening tumors with high metastatic potential. To address this question, we collected tissue from 34 autopsy-derived metastases, samples rarely analyzed in previous studies. These were compared to a separate set of 17 prostatectomy specimens containing 22 foci of CaP associated with 49 examples of high-grade prostatic intraepithelial neoplasia (PIN), a histological precursor of CaP. We compared the loss of heterozygosity (LOH) profiles of high-grade PIN, primary CaP and metastases by analyzing 33 microsatellite markers previously found to have high frequencies of LOH in primary CaP. These markers were on chromosomes 5q, 6q, 7q, 8p, 9p, 10q, 11p, 13q, 16q, 17, 18q and 21q. In addition, markers on chromosomes 4p, 11q, 14q and 20q with no reported LOH in primary CaP were analyzed to determine the frequency of background LOH. In PIN lesions, the rate of LOH was significant only at D5S806 (20%) and D16S422 (29%). In addition, different PIN lesions within the same prostate gland were genetically diverse, indicating divergent evolution of synchronous neoplastic precursor lesions. LOH frequency was progressively higher in primary CaP and metastatic lesions. In primary CaP, significant losses occurred at the 8p, 10q, 11p, 16q, 17p, 18q and 21q loci (range 17-43%). Distinct patterns of LOH frequencies were observed in primary CaP compared with metastases. Although some loci (D16S422, D17S960, D21S156) showed similar frequencies of LOH in primary CaP and metastatic CaP, most other loci showed up to 7-fold metastasis-related increases. The metastatic samples revealed previously unrecognized prostate cancer LOH at D5S806, D6S262, D9S157, D13S133 and D13S227. These significant stage-specific differences in LOH frequency specify genetic loci that may play key roles in CaP progression and could represent clinically useful biomarkers for CaP aggressiveness.

Adenocarcinoma↗
PubMed2001

The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California. METHODS: The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. RESULTS: Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01). CONCLUSIONS: We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Genetic testing of breast and ovarian cancer patients: clinical characteristics and hormonal risk modifiers.

OBJECTIVES: Carriers of the mutations 185delAG and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene have a substantial life-time risk for breast and ovarian cancers (BC and OC). The aim of the study was to identify the clinical features and the hormonal risk modifiers in mutation carriers and the implication in suggested guidelines for treatment decisions in BRCA1/2 carrier patients. STUDY DESIGN: Breast and/or ovarian cancer patients from the Oncology and Cancer Genetic clinics were tested for the three Ashkenazi founder mutations: 87 patients were identified as carriers of one of these mutations. Clinical presentation and age at onset were correlated with the mutations, in patients with bilateral BC or BC and OC, the length of time that elapsed between the diagnosis of the two cancers was recorded. We compared BC and OC patients with regard to ages at menarche, first pregnancy and menopause, number of pregnancies and deliveries, the use of oral contraceptives, hormonal replacement therapy and fertility treatments. RESULTS: The carriers of the three BRCA1/2 Ashkenazi founder mutations did not differ in clinical presentation nor age at onset. Forty-three patients (74.1%) of 58 BC patients were diagnosed between the ages 30 and 50, only four (6.9%) patients were diagnosed after age 60. Of BC patients diagnosed before age 35, 63.6% developed second BC as compared to 25.5% of those diagnosed after age 35. Ovarian cancer was diagnosed after age 45 in 89.7% of the patients, only one patient was diagnosed under the age of 40. Oral contraceptives use was documented in 61.3% of BC patients as compared to 11.8% of OC patients. Other hormonal factors did not differ between the two groups. CONCLUSIONS: The carriers of the three Ashkenazi founder mutations should be considered at the same risk for BC and for OC and treatment options should be the same. Mutation carriers diagnosed with BC before the age of 35 are at a very high risk for developing second breast cancer. Most ovarian cancers in carriers were diagnosed after age 45, and prophylactic oophorectomy should be postponed to the age of 45. Oral contraceptives might elevate the risk of BC in mutation carriers.

Adult↗
PubMed2006

Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis.

A common feature of all the known cancer genetic syndromes is that they predispose only to selective types of malignancy. However, many of the genes mutated in these syndromes are ubiquitously expressed, and influence seemingly universal processes such as DNA repair or cell cycle control. The tissue specificity of cancers that arise from malfunction of these apparently universal traits remains a key puzzle in cancer genetics. Mutations in DNA mismatch repair (MMR) genes cause the most common known cancer genetic syndrome, hereditary non-polyposis colorectal cancer, and the fundamental biology of MMR is one of the most intensively studied processes in laboratories all around the world. This review uses MMR as a model system to understand mechanisms that may explain the selective development of tumors in particular cell types despite the universal nature of this process. We evaluate recent data giving insights into the specific tumor types that are attributable to defective MMR in humans and mice under different modes of inheritance, and propose models that may explain the spectrum of cancer types observed.

Animals↗
PubMed1987

In vitro hyperdiploidy in head and neck cancer. A genetic predisposition?

The role of heredity in the cause of head and neck cancer has not been clarified. Contrary to the autosomal-dominant heritable cancer syndromes, there is no clear genetic pattern seen in oropharyngeal or laryngeal squamous cell carcinoma. Pedigree data demonstrating clusters of affected relatives suggest that some head and neck squamous cell cancers result from an interaction between environmental factors and germinal predisposition. Though no genetic marker has been described for head and neck epidermoid carcinomas, some heritable single tumor syndromes demonstrate increased amounts of hyperdiploidy (defined as a metaphase with more than 46 chromosomes exclusive of 92) in in vitro cultures of dermal fibroblasts. In the present study, dermal fibroblasts were cultured from 30 patients with biopsy-proved oropharyngeal and laryngeal squamous cell cancer. Compared with the percentage of cells with in vitro hyperdiploidy (IVH) of 0% to 1% in 155 clinically normal individuals without a family cancer history, 13 (43%) of these 30 patients had significantly elevated (7% to 12%) IVH. Six of the seven clinically affected women had IVH, a proportion significantly greater than that for the men. In vitro hyperdiploidy remained stable for each assayed cell line from the third through sixth passage. Each patient's IVH percentage of dermal and oropharyngeal fibroblasts remained nearly constant varying 0% to 1%. The stability of the hyperdiploid fraction independent of the biopsy site eliminates local factors as the sources of the elevated IVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Inherited genetic susceptibility to breast cancer.

Inherited genetic susceptibility to breast cancer can be due both to genes which confer a high degree of risk and to polygenes which have a smaller effect on disease risk. An estimated 5-10% of breast cancer is considered to be due to mutations in genes conferring high risk which results in hereditary patterns of disease. Two major breast cancer susceptibility genes, BRCA1 and BRCA2, which were identified using linkage analysis in large extended breast and/or ovarian cancer pedigrees, are estimated to account for the majority of large families with breast/ovarian cancer predisposition and about two-thirds of large breast cancer families. The associated lifetime risk for breast cancer in mutation carriers ranges from 40% to 90%, depending on the extent of family history and the population. Other genetic factors, such as HRAS or CAG repeats of AR, as well as reproductive and hormonal factors may therefore modify cancer risk. Women at particularly high risk of developing breast cancer represent a group in whom expensive and rigorous screening programmes are cost-effective and who may benefit from trials of chemoprevention. There are only preliminary data on the efficacy of increased surveillance and on risk reduction due to prophylactic surgery. However, for chemoprevention to be equivalent to prophylactic mastectomy, it will be necessary to strive for an equivalent reduction. The efficacy of chemoprevention in this high-risk population is unknown. Existing and new agents for chemoprevention need to be carefully assessed in properly designed clinical trials among such women. In the process, other factors modifying the penetrance in mutation carriers need to be taken into account in order to evaluate the true effect of the chemopreventive agents. Polygenes confer much lower levels of risk and may be relevant for risk assessment when the effects of multiple loci, possibly in conjunction with environmental factors, are understood and quantified. At present, it seems unlikely that the genetic information at single polygenes will be clinically relevant for risk assessment and management.

Biomarkers, Tumor↗
PubMed1995

Age-specific oncogenesis: the genetics of cancer susceptibility.

Cancer is considered to be a multifactorial disease in which a host cell is transformed from normal to malignant as a result of complex interactions of external (environmental) stimuli and cancer-predisposing or cancer-suppressing genes. Although certain chemical carcinogens and ionizing radiation are known to cause specific alterations at the level of the gene, other correlations are less clear. Not infrequently, cancer is found to aggregate in families in an apparently nonrandom fashion. It has been through the study of such families that our understanding of the genetic events leading to cancer has developed. Both common and rare tumors may occur together in familial-cancer families. Frequently, tumors occur at an earlier age than one would expect in the general population; often, multiple tumors of different organs develop in a particular affected family member. Recent advances in the genetics of familial cancer syndromes have led to the possibility to perform genetic testing on unaffected relatives who might carry a genetic defect that predisposes them to cancer. Complex ethical, social, and legal implications arise from these new technical advances.

Age Factors↗
PubMed1999

Broadsheet number 52: Molecular genetics of colorectal cancer.

The molecular genetics of colorectal cancer is presented in an order that ascends from the basic to the applied: molecular mechanisms, morphogenesis, classification and diagnosis. Major consideration is given to the nature of genetic instability and the role of this mechanism in driving neoplastic progression. It is shown how the fundamental principle of genetic instability cuts across applied research, tissue diagnosis and clinical management with respect to both sporadic and inherited forms of colorectal cancer.

Adenocarcinoma↗
PubMed2002

Worry and attitude of men in at-risk families for prostate cancer about genetic susceptibility and genetic testing.

BACKGROUND: The aim of this study was to evaluate worry about genetic susceptibility and the attitude of men with family history of prostate cancer (CaP) toward genetic testing. METHODS: Three hundred seventy-five eligible first-degree relatives (FDR) of men with CaP, were asked to participate in a screening and to fill out a survey covering the worry about genetic susceptibility and interest in genetic testing. RESULTS: Of the 375 candidates contacted, 277 completed the survey, and had undergone PSA measurement. Sixty-four percent worried a little or not at all about inherited predisposition to CaP, while the remainder worried a lot or extremely. The candidates who worried a lot or extremely were men with high levels of durable anxiety disposition (STAI trait), who had undergone a previous screening procedure and men with sons. Ninety-eight percent of men expressed their interest in undergoing genetic testing. The most motivated candidates to have the test done were men with several relatives with CaP. CONCLUSIONS: The level of worry about genetic susceptibility was low and there was a concrete interest in genetic testing in FDR of men with CaP. This interest increased with the number of CaP in the family.

Adult↗
PubMedDate not supplied

[Genetics and cancers].

Explore the source record for details and available documents.

Genetic Diseases, Inborn↗
PubMed1982

Aging and cancer as genetic phenomena.

Although the most frequently seen forms of cancer and the changes of senescence have in common the fact that they both occur in old age, their mechanisms are thought to be completely different. Because cancer is usually due to avoidable external agents (such as cigarettes, sunlight, peculiarities of diet, and certain particular hazards of the work place), it is considered a preventable disease. Many of the changes of senescence seem to be simply the inevitable corollary of our innate program of development; homo sapiens is designed to become an optimal, maximally viable product in the late teens, at the time of sexual maturity, and the same processes that lead to this optimalization also lead to a diminished fitness in later life. Although we may eventually abolish most sources of cancer, we should not expect to abolish senescence.

Adolescent↗
PubMed1993

UV-induced mutations in a shuttle vector replicated in repair deficient trichothiodystrophy cells differ with those in genetically-related cancer prone xeroderma pigmentosum.

Trichothiodystrophy (TTD) is a rare genetic disease associated in approximately 50% of patients with DNA repair deficiency analogous to that found in xeroderma pigmentosum group D (XP-D) patients. Although XP-D patients exhibit a very high level of skin cancer on sun-exposed parts, TTD is not associated with cancer. We analysed UV-induced mutations in TTD cells and compared them to data in XP-D in order to determine if the molecular mechanisms of mutagenesis can explain the discrepancies between these two syndromes. We first immortalized a fibroblast TTD line with an ori(-)-SV40 plasmid. To investigate the kinds of mutations induced in TTD cells, we used an UV-irradiated (at 254 nm) shuttle vector carrying the supF tRNA gene as a target. We compared our data with those published by others with the same pZ189 vector in normal and XP-D fibroblast lines (Bredberg et al., Proc. Natl. Acad. Sci. USA, 83, 8273-8277; Seetharam et al., J. Clin. Invest., 80, 1613-1617). The frequency of mutants increased linearly with UV dose and the slope was > 4 times steeper in TTD cells than that observed in normal cells. The mutation frequency was almost identical between XP-D and TTD cells. Sequence analysis of the supF tRNA gene showed that 96% of mutations obtained in TTD cells are base substitutions. Single base substitutions were found in 62% of mutants in TTD cells while they corresponded to 86% in XP-D cells. The frequency of multiple mutations in TTD cells (26%) was similar to that in normal cells (27%) and much higher than that in XP-D cells (9%). Despite the fact that the same gene is mutated in TTD and XP patients, the molecular characteristics of mutagenesis are not identical. The fact that the frequency of mutations in TTD and XP cells are similar shows that a high level of UV-induced mutations is therefore not always directly related to cancer-proneness. Other factors such as catalase activity and immuno-surveillance may intervene in cancer incidence.

Base Sequence↗
PubMed2002

Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result.

The aim of this prospective study was to evaluate the consequences of the disclosure of a positive genetic test result to patients affected with cancer. Personal repercussions and patients' behavior with the transmission of their results to relatives were considered. We conducted semistructured interviews with 23 cancer patients identified as carriers of a cancer-predisposing mutation for hereditary breast ovarian or nonpolyposis colorectal cancers, 1 month after the disclosure of the test result. Eight patients spontaneously expressed distressed reactions ("you no longer feel cured"), and 14 patients reported at least one negative feeling (dissatisfied, discouraged, unhappy, or worried), despite expecting to be a carrier. Sixteen patients expressed concerns about the risk of developing another cancer, and 18 were concerned for their children's future, in that they may carry the mutation and develop a cancer. Although 8 patients found that disadvantages of knowing their genetic status outweighed the advantages, all but 1 did not regret having undergone genetic testing. All of the patients transmitted their results to at least one close relative. Although 6 of them expressed difficulties in being the only person who could transmit the information and 9 said it was a heavy responsibility, all except 1 did not want someone else to have to inform their families. Our results illustrate the potential negative impact of diagnostic genetic testing in patients with cancer. This includes distressed reactions and difficulties in transmitting their results to relatives. Future large-scale studies are warranted to confirm our findings.

Adaptation, Psychological↗