Survival in women with ovarian cancer with and without microsatellite instability.

PURPOSE OF INVESTIGATION: Microsatellite instability (MSI) is a hallmark of defective mismatch repair and is present in approximately 20% of ovarian cancers. It is not known if the presence of MSI predicts survival in women with epithelial ovarian cancer. MATERIALS AND METHODS: Cases of epithelial ovarian cancer were ascertained from a population-based study in Ontario and tumour samples were tested for MSI, using five MSI markers. Patients were divided into MSI-high and MSI-low/normal, according to National Cancer Institute criteria. The authors compared the prevalence of specific prognostic factors in the two subgroups, including age, grade, stage, and histology. They estimated the hazard ratio for death from ovarian cancer associated with MSI-high and with other prognostic factors using a multi-variate analysis. RESULTS: A total of 418 ovarian cancer patients were included. One hundred and twenty-seven (19.7%) cancers were MSI- high. Subgroup analyses did not reveal any statistically significant differences for pathologic features associated with MSI status. No survival difference was seen according to MSI status. CONCLUSIONS: The presence of MSI in ovarian cancer is not associated with survival.

Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers.

BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management (CRM) strategies varies by service provider. Using a registry-based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling (GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi-squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers.

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

BACKGROUND: Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer. METHODS: The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women. RESULTS: Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers. CONCLUSIONS: Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer.

BACKGROUND: Previous studies have suggested that cancers of the breast and prostate cluster in families and that the presence of both diseases in a family may be associated with increased risk of breast cancer. PURPOSE: Our purpose was to evaluate whether 1) prostate cancer aggregates in families with postmenopausal breast cancer, 2) families with cancers of the breast and prostate are the same ones as families with cancers of the breast and ovary, and 3) a family history of prostate cancer is associated with increased risk of postmenopausal breast cancer. METHODS: We analyzed data from a large prospective cohort study of Iowa women that were (at baseline) aged 55-69 years in 1986. At the third follow-up survey in 1992, self-reported data on family history of breast, ovarian, and prostate cancers in parents and siblings were provided by 30,883 women. Additional information was collected to ascertain whether the age-of-onset of breast cancer in mothers or sisters was before or after the age of 45 years. Cancer occurrence was documented using the State Health Registry of Iowa. RESULTS: History of prostate cancer in their father or a brother was reported by 3384 (11.0%) of the women, and a total of 4090 women (13.2%) reported breast cancer in their mother or a sister. A positive family history of both cancers was reported by 556 women, significantly (two-sided P < .001) greater than the 457 women expected if the family histories were independent. The aggregation of breast, prostate, and ovarian cancers was reported by 22 participants, greater than the 2.7 expected (two-sided P < .0001). During 6 years of follow-up, 578 breast cancers were identified in the cohort at risk. Compared with women without a family history of either cancer, women with a family history of breast cancer had a relative risk (RR) of 1.37 (95% confidence interval [CI] = 1.06-1.79) if the affected relative had onset after the age of 45 years, and an RR of 1.71 (95% CI = 1.13-2.61) if the affected relative had onset at or before the age of 45. A family history of prostate cancer in the absence of a family history of breast cancer was associated with an RR of 1.19 (95% CI = .90-1.56). However, a family history of both breast and prostate cancers was associated with RRs of 2.06 (95% CI = 1.23-3.45) and 2.35 (95% CI = .97-5.67) for breast cancer onset in relatives of greater than 45 and less than or equal to 45 years, respectively. CONCLUSIONS: These observations are concordant with recent reports that suggest a shared familial risk (inherited or environmental) for these hormone-dependent malignancies.

Genetic services for familial cancer patients: a survey of National Cancer Institute cancer centers.

In the past decade, significant progress has been made in understanding the genetic component of familial cancers. Genes associated with familial colon and breast cancers have recently been isolated and molecular diagnostic tests are expected to become available in the near future. Clinicians now have the opportunity to recognize and counsel individuals with elevated risk of cancer by identifying risk factors and genes associated with cancer predisposition. The rapid advances in molecular technology are a direct challenge to the medical community and cancer centers to supply specialized clinical services for familial cancers. We sought to ascertain the activities of cancer centers in the development of programs and the provision of genetic services for familial cancer. We surveyed 41 centers with National Cancer Institute (NCI) cancer center support grants. One half of the centers responding (17 of 34) reported that they provide some genetic services for familial cancer. About one half of these 17 centers (eight [57%] of 14; the three remaining clinics that responded had incomplete information on this indicator) see a variety of patient types on a small scale (fewer than 100 patients per year), and most provide four basic clinical evaluations: medical evaluation, cancer risk assessment, genetic counseling, and pedigree analysis. Staffing of each center varied widely, as did the types of screening services offered (including molecular diagnostic testing). Several centers (six [35%] of 17) indicated that they were in the developmental stages for serving familial cancer patients, and many seem to be increasing their activities in this area. The remaining 17 NCI-supported centers that responded, however, currently provide no genetic services for familial cancers. The results of this survey suggest that there is interest in developing clinical programs for familial cancers by NCI-supported cancer centers, but most of these programs are in developmental stages. A base line has been established to monitor future progress for the provision of cancer genetic services.

Dietary fat and postmenopausal breast cancer.

BACKGROUND: Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal. PURPOSE: The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa. METHODS: Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered. RESULTS: After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association. CONCLUSIONS: These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer. IMPLICATIONS: Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations.

Genetic analysis of mammographic breast density in adult women: evidence of a gene effect.

BACKGROUND: The appearance of the female breast viewed by mammography varies considerably from one individual to another because of underlying differences in the relative proportions of fat, connective tissue, and glandular epithelium that combine to create a characteristic pattern of breast density. An association between mammographic patterns and family history of breast cancer has previously been reported. However, this association has not been found in all studies, and few data are available on possible genetic components contributing to mammographic breast density. PURPOSE: Our purpose was to estimate familial correlations and perform complex genetic segregation analyses to test the hypothesis that the transmission of a major gene influences mammographic breast density. METHODS: As part of a cohort study (initiated in 1944) of families with a history of breast cancer, the probands' female relatives who were older than 40 years were asked to obtain a routine mammogram. The mammograms of 1370 women from 258 independent families were analyzed. The fraction of the breast volume occupied by radiographically dense tissue was estimated visually from video displays of left or right mediolateral oblique views by one radiologist experienced in mammography who had no knowledge of individual relationships to the probands. Data on breast cancer risk factors were obtained through telephone interviews and mailed questionnaires. Unadjusted and adjusted familial correlations in breast density were calculated, and complex genetic segregation analyses were performed. RESULTS: Sister-sister correlations in breast density (unadjusted and adjusted for age and either body mass index, menopausal status, hormone replacement therapy, waist-to-hip ratio, number of live births, alcohol consumption, or cigarette smoking status) were all statistically significant (r = .16-.27; all P<.05 [two-sided]). Estimated mother-daughter correlations were smaller in magnitude (r = .01-.17) and not statistically significant. Segregation analyses indicate that a major autosomal gene influences breast density. The mendelian transmission of a dominant gene provided the best fit to the data; however, hypotheses involving the inheritance of either a recessive gene or a codominant gene could not be ruled out. The mendelian dominant hypothesis, accounting for 29% of the variability in breast density, suggests that approximately 12% of the population would be expected to carry at least one variant allele of this putative gene. Women who inherit the variant allele would have a mean breast density about twice that of the rest of the population. CONCLUSIONS: Our preliminary findings suggest that, in this cohort of women at risk of breast cancer, mammographic breast density may be genetically influenced.

Twinship and risk of postmenopausal breast cancer.

BACKGROUND: Intrauterine exposure to high levels of endogenous estrogens has been hypothesized to increase the risk of breast cancer. Because estrogens and other pregnancy hormones are substantially elevated in twin pregnancies, and possibly more so in dizygotic twin pregnancies, we evaluated the association between aspects of twin membership (i.e., belonging to a twin pair) and the risk of breast cancer. METHODS: In a cohort of 29 197 postmenopausal Iowa women with no prior diagnosis of cancer (except for nonmelanoma skin cancer), breast cancer risk factors were determined by use of a mailed questionnaire in 1986 (baseline); twin membership, sex of the twin, and zygosity were determined by use of a follow-up questionnaire in 1992. RESULTS: Within the cohort, 1.8% (n = 538) of the women reported being a twin; of these, 24% (n = 130) were monozygotic twins, 63% (n = 337) were dizygotic twins, and 13% (n = 71) did not know their zygosity. From 1986 through 1996, 1230 breast cancers in the cohort were ascertained by linkage to the Iowa Cancer Registry. Compared with singletons, women who belonged to a twin pair were at elevated risk of breast cancer (multivariate-adjusted risk ratio [RR] = 1.72; 95% confidence interval [CI] = 1.22-2.42), with adjustment for educational level, family history of breast cancer, height, body mass index, body fat distribution, age at menarche, age at first live birth, use of hormone replacement therapy, and alcohol use. Multivariate-adjusted risk was elevated (in comparison with singletons) if the sex of the other twin was female (RR = 1.82; 95% CI = 1.20-2.75); however, this risk was limited to female dizygotic twins (RR = 2.14; 95% CI = 1. 21-3.79), since no excess risk was evident for monozygotic twins (RR = 1.04; 95% CI = 0.43-2.50). The risk to women with a male twin was also elevated (RR = 1.49; 95% CI = 0.80-2.78) in comparison with singletons, but this estimate was not statistically significant. CONCLUSIONS: This cohort study lends further support to the theory that there are important intrauterine influences on carcinogenesis of the breast.

Well-done meat intake and the risk of breast cancer.

BACKGROUND: Heterocyclic amines, mutagens formed in meats cooked at high temperatures, have been demonstrated as mammary carcinogens in animals. We conducted a nested, case-control study among 41836 cohort members of the Iowa Women's Health Study to evaluate the potential role of heterocyclic amines and intake of well-done meat in the risk for human breast cancer. METHODS: A questionnaire was mailed to individuals in the cohort who had breast cancer diagnosed during the period from 1992 through 1994 and a random sample of cancer-free cohort members to obtain information on usual intake of meats and on meat preparation practices. Color photographs showing various doneness levels of hamburger, beefsteak, and bacon were included. Multivariate analysis was performed on data from 273 case subjects and 657 control subjects who completed the survey. RESULTS: A dose-response relationship was found between doneness levels of meat consumed and breast cancer risk. The adjusted odds ratios (ORs) for very well-done meat versus rare or medium-done meat were 1.54 (95% confidence interval [CI]=0.96-2.47) for hamburger, 2.21 (95% CI=1.30-3.77) for beef steak, and 1.64 (95% CI=0.92-2.93) for bacon. Women who consumed these three meats consistently very well done had a 4.62 times higher risk (95% CI=1.36-15.70) than that of women who consumed the meats rare or medium done. Risk of breast cancer was also elevated with increasing intake of well-done to very well-done meat. CONCLUSIONS: Consumption of well-done meats and, thus, exposures to heterocyclic amines (or other compounds) formed during high-temperature cooking may play an important role in the risk of breast cancer.

Evidence for mendelian inheritance in the pathogenesis of lung cancer.

Segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer proband. Results indicated compatibility of the data with mendelian codominant inheritance of a rare major autosomal gene that produces earlier age of onset of the cancer. Segregation at this putative locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60, respectively. The gene was involved in only 22% of all lung cancers in persons up to age 70, a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco.

Medical history risk factors for non-Hodgkin's lymphoma in older women.

BACKGROUND: It has been suggested that certain medical conditions and drug exposures might suppress the immune system and increase the risk of developing non-Hodgkin's lymphoma (NHL). PURPOSE: We investigated whether specific medical conditions and drug exposures were associated with the risk of NHL in a cohort of older women who were enrolled in the Iowa Women's Health Study. METHODS: A cohort of 41837 women, 55-69 years of age at baseline, was followed prospectively for the development of cancer from 1986 through 1992. These women had completed a baseline questionnaire in January 1986 that inquired about the occurrence and age at onset of specific medical conditions, about family history of cancer, and about the use of selected medications. Follow-up questionnaires were mailed to the women in 1987, 1989, and 1992. Incident cancers and deaths were ascertained through linkages to state and national databases. For most analyses, women with a self-reported history of cancer at baseline (n = 3903) were excluded. Relative risks (RRs) and 95% confidence intervals (CIs), adjusted for age or for age and other variables, were used as a measure of the association between NHL and medical history factors. Reported P values are two-sided. RESULTS: One hundred fourteen incident cases of NHL were identified in the cohort during follow-up. A history of adult-onset diabetes mellitus (i.e., first diagnosed after the age of 30 years) was associated with an increased risk of developing NHL (age-adjusted RR = 2.18; 95% CI = 1.22-3.90). In addition, there was an association between the duration of adult-onset diabetes and increasing risk of NHL (P for trend = .004), with an age-adjusted RR of 2.90 (95% CI = 1.07-7.90) for women with a diagnosis of diabetes for 15 or more years compared with women with no diagnosis of diabetes. Women with a history of blood transfusion were also at increased risk for the development of NHL (age-adjusted RR = 1.95; 95% CI = 1.33-2.85). The risk estimates for diabetes and transfusion history were independent of each other and were not changed substantially after adjustment for other risk factors. History of a previous cancer (excluding hematopoietic and lymphatic cancers) was associated with an increased risk of NHL (age-adjusted RR = 1.92; 95% CI = 1.21-3.06); this risk estimate was attenuated somewhat after adjustment for a history of diabetes, transfusion history, and other major risk factors (RR = 1.66; 95% CI = 1.02-2.69). No statistically significant associations were found between NHL and a history of chronic colitis, nonestrogen steroid use, use of exogenous estrogens, or use of thyroid medications. CONCLUSIONS AND IMPLICATIONS: A history of adult-onset diabetes mellitus, blood transfusion, and a history of cancer (or its treatment) appear to be independent risk factors for NHL in older women.

Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.

Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's Health Study.

Antioxidant micronutrients, including vitamin E, vitamin C, the carotenoids, and selenium, defend the body against free radicals and reactive oxygen molecules, suggesting a potential for these dietary components in cancer prevention. To investigate whether high intakes of antioxidant micronutrients protect against colon cancer in humans, we analyzed data from a prospective cohort study of 35,215 Iowa women aged 55-69 years and without a history of cancer who completed a dietary questionnaire in 1986. Through 1990, 212 incident cases of colon cancer were documented. Adjusted for age, total vitamin E intake was inversely associated with the risk of colon cancer (P for trend < 0.0001); the relative risk for the highest compared to the lowest quintile was 0.32 [95% confidence interval (95% CI) 0.19, 0.54]. Further adjustment for total energy intake and other risk factors in proportional hazards regression had little effect on these estimates. The association was not uniform across age groups: the multivariate relative risk of colon cancer for the highest compared to the lowest quintile of total vitamin E intake was 0.16 (95% CI 0.04, 0.70) for those 55-59 years old, 0.37 (95% CI 0.12, 1.16) for those 60-64 years old, and 0.93 (95% CI 0.27, 3.25) for those 65-69 years old. Multivariate-adjusted relative risks among women with higher total intakes of vitamins A and C and beta-carotene, and among users of selenium supplements, were not significantly different from 1.0. These prospective data provide evidence that a high intake of vitamin E may decrease the risk of colon cancer, especially in persons under 65 years of age.

Lung cancer detection and prevention: evidence for an interaction between smoking and genetic predisposition.

The initiation and promotion of cancer is thought to result from a series of genetic mutations, some of which may be inherited. Our analysis of 337 lung cancer families suggested that, after allowing for an individual's pack-years of tobacco use, the pattern of disease was best explained by Mendelian codominant inheritance of an allele that produced earlier age of onset. Since lung cancer rarely occurs in the absence of exposure to tobacco, differences in the prevalence of smoking across generations could have a profound influence on the fit of genetic models. In the present study, families were partitioned into two groups, based on the birth cohort of the proband, i.e., born before World War I (age at death, greater than or equal to 60 years) or born after World War I (age at death, less than 60 years). This partition was chosen because the year 1915 signaled the start of the dramatic rise in tobacco use in the United States. In younger proband families, in which parents were more likely to smoke, Mendelian codominant inheritance provided the best fit to the data. In older proband families, for whom smoking among parents was less prevalent, the "no major gene" and "environmental" hypotheses were rejected; however, no Mendelian models could be distinguished. If the results on the families with the most homogeneous exposure to tobacco across generations (born after World War I) reflect the true underlying biology, then the influence of genetic factors in the pathogenesis of lung has been underestimated; the cumulative probability of lung cancer at age 80 for a noncarrier of the gene, at the average level of tobacco consumption, is close to zero, implying that virtually all lung cancer occurs among gene carriers. Identification of this putative genetic factor has profound implications for the detection and prevention of lung cancer.

Lung cancer risk reduction after smoking cessation: observations from a prospective cohort of women.

PURPOSE: We conducted this study because the duration of excess lung cancer risk among former smokers has been inconsistently reported, doubt has been raised regarding the population impact of smoking cessation, and differential risk reduction by histologic cell type after smoking cessation needs to be confirmed. METHODS: The Iowa Women's Health Study is a prospective cohort study of 41,836 Iowa women aged 55 to 69 years. In 1986, mailed questionnaires were used to collect detailed smoking history. Age-adjusted lung cancer incidence through 1999 was analyzed according to years of smoking abstinence. Relative risks were estimated using Cox regression analysis. RESULTS: There were 37,078 women in the analytic cohort. Compared with the never smokers, former smokers had an elevated lung cancer risk (relative risk, 6.6; 95% confidence interval, 5.0 to 8.7) up to 30 years after smoking cessation for all former smokers. However, a beneficial effect of smoking cessation was observed among recent and distant former smokers. The risk of adenocarcinoma remained elevated up to 30 years for both former heavier and former lighter smokers. CONCLUSION: The risk for lung cancer is increased for both current and former smokers compared with never smokers and declines for former smokers with increasing duration of abstinence. The decline in excess lung cancer risk among former smokers is prolonged compared with other studies, especially for adenocarcinoma and for heavy smokers, suggesting that more emphasis should be placed on smoking prevention and lung cancer chemoprevention.

Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

Association between keratin and vimentin expression, malignant phenotype, and survival in postmenopausal breast cancer patients.

Pathology observational reports and experimental data suggest that keratin and vimentin intermediate filament (IF) coexpression in breast cancer confers a more aggressive "interconverted" phenotype, expressing both epithelial and mesenchymal markers. In this study, we extended previous observations by measuring the expression of keratin and vimentin, in relation to other selected biomarkers of disease progression, in postmenopausal women with breast cancer. Using immunohistochemical analysis of 54 archival, formalin-fixed, paraffin-embedded invasive breast cancers from a well-defined cohort, we examined relative IF (keratin and vimentin) expression in a semiquantitative fashion and compared these results with other biological markers and survival. By univariate analysis, we found that vimentin expression was inversely associated with keratin expression alone (P = 0.0089) and directly related to histological grade (P = 0.017), nuclear grade (P = 0.027), Ki67 growth fraction (P = 0.024), and epidermal growth factor receptor immunostaining (P = 0.019). The relative expression of keratin and vimentin in approximately similar amounts characterized tumors with the poorest prognosis, as compared with keratin-high/vimentin-negative or keratin-low/vimentin-positive tumors. These latter two groups demonstrated similar Kaplan-Meier survival curves; the former group (keratin and vimentin in approximately similar amounts) demonstrated a poorer survival, with a hazard ratio of 2.1 (95% confidence interval, 0.5-9.6). These data suggest that relative keratin and vimentin IF expression is more indicative of prognosis and tumor phenotype than either IF marker detected independently.

Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women's Health Study.

BACKGROUND: Recent clinical guidelines on the health risks of obesity use body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) and waist circumference, but the waist-hip ratio may provide independent information. METHODS: To assess the joint and relative associations of BMI, waist circumference, and waist-hip ratio with multiple disease end points, we conducted a prospective cohort study of 31,702 Iowa women, aged 55 to 69 years and free of cancer, heart disease, and diabetes, assembled by random sampling and mail survey in 1986. Study end points were total and cause-specific mortality and incidence of site-specific cancers and self-reported diabetes, hypertension, and hip fracture over 11 to 12 years. RESULTS: The waist-hip ratio was the best anthropometric predictor of total mortality, with the multivariable-adjusted relative risk for quintile 5 vs 1 of 1.2 (95% confidence interval, 1.1-1.4), compared with 0.91 (95% confidence interval, 0.8-1.0) for BMI and 1.1 (95% confidence interval, 1.0-1. 3) for waist circumference. The waist-hip ratio was also associated positively with mortality from coronary heart disease, other cardiovascular diseases, cancer, and other causes. The waist-hip ratio was associated less consistently than BMI or waist circumference with cancer incidence. All anthropometric indexes were associated with incidence of diabetes and hypertension. For example, women simultaneously in the highest quintiles of BMI and waist-hip ratio had a relative risk of diabetes of 29 (95% confidence interval, 18-46) vs. women in the lowest combined quintiles. CONCLUSION: The waist-hip ratio offers additional prognostic information beyond BMI and waist circumference.