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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of the p53 gene are now known to be one of the most commonly detected genetic defects among human cancers. Because of its stability, the mutant p53 protein can be detected by immunohistochemical methods. Overexpression of the mutant p53 protein has been suggested as a prognostic indicator for the recurrence of breast cancer. Using a monoclonal antibody to p53, formalin-fixed, paraffin embedded breast cancer tissues retrieved from up to 10 years storage in the archival files were processed for staining. A total of 125 cases was examined p53 overexpression was identified by brown nuclear staining. Clinical parameters studied included estrogen and progesterone receptors, tumor size, nodal status, obesity, stage, and histopathological grade. The only significant association seen for p53 overexpression was with negative estrogen and progesterone receptors. All other clinical parameters studied were independent of p53 overexpression. Thus, p53 overexpression does not appear to be a useful prognostic indicator for recurrence and survival in human breast cancer.
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PMID:p53 protein expression in human breast carcinoma: lack of prognostic potential for recurrence of the disease. 870 54

Numerous factors have been noted to be associated with risk of breast cancer. Indicators of endogenous hormonal alterations are among them: early age at menarche and late age at menopause, nulliparity, late age at first full term pregnancy and obesity in postmenopausal women. Other established risk factors are family history of breast cancer, histologic characteristics of benign tissue, mammographic patterns, exogenous hormones and alcohol consumption. Endogenous indicators may be a reflection of enhanced susceptibility, whereas exogenous exposures can have both independent effects on risk and the ability to interact with markers of inherited susceptibility. In case control studies of breast cancer, family history confers a risk elevation of two to three fold. The higher risk estimate occurs when first degree rather than second degree relatives are affected, or if more than one relative is affected. A relative diagnosed before age 45 increases risk for early-onset breast cancer. These findings have been obtained using either traditional analytic methods for case control data or an alternative strategy, which uses case control status as the predictor variable and models the risk to relatives in a time-dependent fashion. Risk of breast cancer is greater for the mother and sisters of cases than controls. The magnitude of risk increases with 1) decreasing age of diagnosis of the index case 2) additional family members with diagnosed breast cancer and 3) bilateral breast cancer in the index case. Although these two analytic approaches have somewhat different data requirements and may be subject to different biases, the results produced are quite consistent. Mutated p53 in female family members of patients with Li-Fraumeni syndrome was one of the first identified genetic susceptibility markers for breast cancer. Application of segregation and linkage analyses to pedigrees with multiple affected family members successfully focused the search for BRCA1. Recent cloning and sequencing of BRCA1 will allow for its use in risk assessment, diagnostic evaluation and screening of high risk women. BRCA1 appears to be primarily responsible for early-onset breast cancer in high risk families. Rare alleles of H-ras could account for some of the late-onset cases in unselected populations since at least 85% of breast cancer appears to be sporadic, other genetic markers yet to be identified undoubtedly exist.
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PMID:Epidemiology of susceptibility to breast cancer. 889 88

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.
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PMID:Cancer risk factors for selecting cohorts for large-scale chemoprevention trials. 902 95

The two types of endometrial carcinomas are preceded by precancerous lesions. Type I endometrial carcinomas are most commonly encountered in perimenopausal women with the classical risk factors associated with estrogen exposure: obesity, multiparity, diabetes, estrogen treatment, ... Hyperplasia (simple, followed by complex forms without cellular atypias and subsequently by complex hyperplasias with cellular transformation) precede such cancers. Estrogens exert a promoting effect on these lesions but do not initiate them. Progesterone and progestins exert a preventive and protective effect. However, the progressive loss of steroidal receptors is correlated to the progression of tissular anomalies and to the onset of cytogenetic anomalies and to mutations of p53 anti-oncogene. The preventive role of progestin is well established, but their curative beneficial effect on atypical precursors forms of endometrial cancers and on endometrial carcinomas remains controversial. The second type of endometrial cancer appears during the postmenopause and is characterized by an increased invasiveness and a poor prognosis, devoid of identifiable risks factors, these aggressive cancers are not preceded by hormone-sensitive precancerous lesions, but by an intra-epithelial endometrial carcinoma. This lesion appears most often in an atrophic endometrium. Finally, the two types of precancerous states are characterized by distinct gene anomalies suggesting two different pathogenic mechanisms of cancerisation.
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PMID:[Precancerous states of the endometrium: hormonal aspects]. 952 83

This review summarizes data on the occurrence, the trends, and the life-style, environmental, occupational and genetic determinants of pancreatic cancer. Epidemiologic evidence implicates tobacco smoking as one cause. The evidence regarding alcohol consumption is inconsistent. Although both positive and inconclusive findings are encountered, the bulk of the evidence on coffee consumption is negative. Fat intake is linked with obesity and diabetes mellitus, which are risk factors for pancreatic cancer. Fruit and vegetable consumption appears to be protective. No occupational or environmental agent has been confirmed to increase the risk, but epidemiologic evidence is inconsistent, Little is known about the role of genetic polymorphisms of metabolic enzymes in pancreas carcinogenesis. Pancreatic cancer shows high rates of mutations of Ki-ras and losses or mutations of tumor suppressor genes (p53, p16INK4A, and SMAD4/DPC-4). Ki-ras mutations have been associated with life-style factors in relation to pancreatic cancer, but the evidence is still scant and inconsistent.
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PMID:Occurrence, trends and environment etiology of pancreatic cancer. 971 Mar 67

Possible relationships between risk factors, such as obesity and a family history of breast cancer, and prognostic factors of mammary carcinomas were investigated by examining the body mass index of patients and the expression of estrogen (ER) and progesterone receptors (PgR), c-erbB-2 and p53, grade of histology, size of tumors and nodal status of mammary carcinomas. There was no significant difference in the body mass index of premenopausal patients either with or without a family history. For postmenopausal patients, the body mass index was significantly low in patients with a family history compared with patients without a family history. In premenopausal patients with or without a family history and in postmenopausal patients with a family history, there was no significant difference in the body mass index regardless of the mammary carcinoma prognostic factor, such as expression of ER, PgR, c-erbB-2 and p53, grade of histology, size of tumors and nodal status. However, in postmenopausal patients without a family history, body mass index was significantly high for patients with mammary carcinomas that had PgR expression and node metastasis. These results suggest that obesity may affect the PgR status and nodal status of mammary carcinomas in postmenopausal patients without a family history.
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PMID:Obesity affects expression of progesterone receptors and node metastasis of mammary carcinomas in postmenopausal women without a family history. 1033 73

Biological markers associated with in situ carcinoma and atypical intraductal hyperplasia in the breast are examined to help in identifying a subgroup of premalignant lesions whose natural history may be influenced by epigenetic factors. The biomarkers may be used as indices in clinical trials aiming to assess the effect of weight reduction, dietary intervention or hormone replacement therapy on the risk of progression to invasive breast cancer. In the current state of knowledge, the expression of oestrogen receptors, p53, bcl-2 and HER-2 neu oncogenes and the Ki-67 index of proliferative activity, are the most useful biomarkers for this purpose. In situ carcinoma of the breast manifests a variety of morphological phenotypes with specific biological characteristics. There is evidence that only a proportion of premalignant lesions are committed to progression to invasive cancer while other lesions undergo spontaneous regression at the time of the menopause. Cross-cultural studies suggest that it is the late-stage epigenetic promoting factors which are responsible for the high incidence of postmenopausal breast cancer in Western women. Obesity in middle life and the Western diet favour the development of hyperinsulinaemic insulin resistance, and the metabolic-endocrine effects of its concomitants may promote mammary carcinogenesis around the time of the menopause and increase the incidence of invasive cancer after the menopause. Because biomarker changes in premalignant lesions are nearer in time to these promoting influences, they could provide intermediate endpoints for testing the hypothesis.
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PMID:Premalignant breast lesions: role for biological markers in predicting progression to cancer. 1050 26

Endometrial cancers are generally divided into at least two different pathogenetic types. One occurs from the proliferative endometrium, depending on continuous estrogen stimulation, while the other is not related to the stimulation and occurs from the atrophic endometrium of older post-menopausal women. In order to assess the risk factors for endometrial carcinoma (EC), a case-control study with 136 Japanese women having EC and with 376 healthy controls for ECs in Japan, together with an immunohistochemical analyses on p53, estrogen (ER) and progesterone receptors (PR) of EC patients was undertaken. Nulliparity, increased BMI, hypertension, diabetes mellitus, later age at menopause and personal cancer history were all seen predominantly in the EC group. Frequency of irregular menses, polycystic ovary syndrome (PCOS) and obesity in the EC patients under 40-year old was significantly higher than the control group. Immunohistochemical expressions of ER (P<0.05) and PR (P<0. 01) were more frequently recognized in the EC of the pre-menopausal than in the post-menopausal patients. On the other hand, p53 overexpression was detected in 27.2% of the post-menopausal EC group, while only found in 7.1% of the pre-menopausal EC group. These findings indicate that possible factors related to endometrial carcinogenesis are different between the pre- and post-menopausal EC patients. Namely, untreated ovarian dysfunction such as PCOS with unopposed estrogenic action in the endometrium may be associated with development and growth of EC in younger women, yet abnormality of p53 gene may be more concerned with the development of the post-menopausal EC, independently of sex steroid influence.
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PMID:A case-control study of uterine endometrial cancer of pre- and post-menopausal women. 1060 98

Although several studies have reported that p53 overexpression is associated with poor survival from endometrial cancer, this relationship might be confounded by a number of possible factors. The objective of this study was to examine the prognostic role of p53 overexpression in endometrial cancer when a panel of well-selected potential confounding factors were controlled. One hundred and twenty-five endometrial cancers were examined for p53 overexpression by immunohistochemistry (IHC). Demographic and clinical data, including age at diagnosis, race, residence, tumor grade, surgical stage, and other possible confounding factors for endometrial cancer such as diabetes, family history of cancer, hypertension, hormone replacement therapy (HRT), and obesity were collected from medical charts and pathologic reports. Survival status was determined at the end of follow-up. The Kaplan-Meier method was used to derive the survival curve, while the log-rank test was used to compare curves for two or more groups of patients. The proportional hazards regression model was used to obtain maximum likelihood estimates of relative risks (RR) and their 95% confidence intervals. Compared to the p53 nonaltered group, the presence of p53 overexpression in endometrial carcinoma was related to significantly decreased patient survival. High nuclear grade and high FIGO stage were associated with poor survival. No obvious association was found between survival and study site, race, age, and other potential risk factors of endometrial cancer. Only two variables (p53 and stage) were significantly associated with poor survival in the multivariate proportional hazards analysis. Overexpression of p53 was found to be the most significant predictor of specific survival. The relative risk for p53 overexpression was 7.46 (95% CI: 4.26-13.1) and for late stage was 4.35 (95% CI: 1.91-9.92). We conclude that p53 overexpression is the most important predictor for patient survival when a panel of well-selected potential confounding factors are taken into account. Patients with endometrial cancers who have p53 overexpression have a seven-fold higher risk of dying from disease compared to those without p53 overexpression. Whether detection of p53 alteration may serve as an indicator of high-risk patients for whom more aggressive adjuvant chemotherapy may be considered needs to be explored in the future.
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PMID:p53 as a significant prognostic marker in endometrial carcinoma. 1124 Jun 63

Although the mortality and incidence of cervical cancer have been decreasing, those of uterine-body, or endometrial, cancer have been increasing. The proportion of endometrial cancer was reported to have become 33.6% of primary uterine cancers in 1995. Infection with certain types of human papilloma virus (HPV) is considered to be etiologically important for the occurrence of cervical cancer. Because HPV is sexually transmitted, some risk factors for cervical cancer are associated with certain kinds of sexual behavior such as a young age at first intercourse, multiple partners, and infrequent use of barrier-type contraceptives such as condoms. Frequent conceptions and deliveries and histories of sexually transmitted diseases like infection with herpes simplex virus type 2 or chlamydia also have been suggested to be associated with the risk of cervical cancer. Smoking habits and infrequent intake of vegetables and fruits may be related to the increased risk of cervical cancer by supporting persistent infection of HPV through impaired immunological function. Although host factors such as a variant of a tumor suppressor gene like p53 have been assessed in terms of the risk of cervical cancer, these are not yet clearly elucidated. Estrogen stimulation of the endometrium unopposed by progesterone stimulation, namely, unopposed estrogen stimulation, is thought to be involved in the etiology of endometrial cancer. Frequent intake of animal fat, obesity or being overweight, infertility, and histories of diabetes mellitus, hypertension, and polycystic ovary syndrome have been reported to be risk factors for endometrial cancer, and they are thought to increase unopposed estrogen stimulation. Estrogen replacement therapy for postmenopausal symptoms, tamoxifen therapy for breast cancer, and taking sequential-type oral contraceptives have been shown to be exogenous risk factors for endometrial cancer in that they increase unopposed estrogen stimulation to endometrium.
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PMID:[Recent progress in epidemiologic research of uterine cancer]. 1124 42


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