Incidence of breast cancer in first-degree female relatives of men with newly diagnosed prostate cancer

Prostate cancer is the most common incident cancer and the second leading cause of death in men in the United States. Although numerous attempts have been made to identify risk factors associated with prostate cancer, the results have been inconsistent and conflicting. The only established risk factors are age and ethnicity. A positive family history of prostate cancer has also been shown to increase the risk two- to three-fold among close relatives.^ There are several similarities between breast and prostate cancer that make the relationship between the two of interest. (1) Histologically, both cancers are predominantly adenocarcinomas, (2) both organs have a sexual and/or reproductive role, (3) both cancers occur in hormone-responsive tissue, (4) therapy often consists of hormonal manipulation, (5) worldwide distribution patterns of prostate and breast cancer are positively correlated.^ A family history study was conducted to evaluate the aggregation of prostate cancer and co-aggregation of breast cancer in 149 patients referred to The University of Texas, M.D. Anderson Cancer Center with newly diagnosed prostate cancer. All patients were white, less than 75 years of age at diagnosis and permanent residents of the United States. Through a personal interview with the proband, family histories were collected on 1,128 first-degree relatives. Cancer diagnoses were verified through medical records or death certificate. Standardized incidence ratios were calculated using a computer program by Monson incorporating data from Connecticut Tumor Registry.^ In this study, familial aggregation of prostate cancer was verified only among the brothers, not among fathers. Although a statistically significant excess of breast cancer was not found, the increased point estimates in mothers, sisters and daughters are consistent with a co-aggregation hypothesis. Rather surprising was the finding of a seven-fold increased risk of prostate cancer and a three-fold increased risk of breast cancer among siblings in the presence of a maternal history of any cancer. Larger family history studies including high risk (African-Americans) and lower-risk groups (Hispanics) and incorporating molecular genetic evaluations should be conducted to determine if genetic differences play a role in the differential incidence rates across ethnic groups. ^

Evaluation of Recurrence Risks for Left-Sided Cardiac Lesions

It is widely accepted that hypoplastic left heart syndrome (HLHS), aortic valve stenosis with or without bicuspid aortic valve (AS/BAV) and coarctation of the aorta (CoA) occur in families more commonly with each other than with any other congenital heart defect (CHD). Genetic counseling for CHDs is currently based on empiric risk estimates derived from data collected on all types of CHDs between 1968 and 1990. Additionally, for the specific group of defects described above, termed left-sided lesions, estimates are available for sibling recurrence. Utilizing family history data from 757 probands recruited between 1997 and 2007 from The Children’s Hospital of Philadelphia, this study reassessed the pre/recurrence risks for LSLs specifically. Sibling pre/recurrence risks for HLHS (5.5%, 95% CI: 3.1%-8.9%), CoA (4.0%, 95% CI: 2.1%-6.7%), and AS/BAV (6.0%, 95% CI: 3.3%-9.8%) were higher than currently quoted risks based on sibling data for individual LSLs. Additionally, the prevalence of BAV in 202, apparently unaffected, parents of 134 probands was assessed by echocardiography. BAV, which occurs at a frequency of 1% in the general population, was found to occur in approximately 10% of parents of LSL probands. Lastly, among affected first-degree relative pairs (i.e. siblings, parent-offspring), the majority (65%-70%) were both affected with a LSL. Defect specific concordance rates were highest for AS/BAV. Together, these findings suggest that over the past 20 years with changing diagnostic capabilities and environmental/maternal conditions (e.g. folic acid fortification, increased maternal diabetes and obesity) recurrence risks may have increased, as compared to current LSL specific risk estimates. Based on these risk estimate increases and prior studies, a protocol for screening first-degree relatives of LSL probands should be devised.

A case-control study of bilateral compared with unilateral breast cancer

Approximately 10 to 15% of breast cancer patients develop a primary cancer in the contralateral breast. This study examined differences between women with unilateral compared with bilateral primary breast cancer. It focused on hormonal factors and family history, and evaluated the prevalences of invasive lobular histology and the replication error phenotype in the tumors. ^ Cases (n = 82) were patients at M.D. Anderson Cancer Center (MDACC) in Houston, Texas diagnosed with primary breast cancer in each breast between 1985 and 1994 inclusive. Controls (n = 82) were MDACC patients with primary cancer in a single breast diagnosed during the same interval, individually matched to cases. Data were obtained by in-person and/or telephone interview with the patient and/or proxy. Replication error phenotype was determined from archival tissue. ^ Diagnosis of breast, but not ovarian, cancer in a female first-degree relative (FFDR) was a strong risk factor for bilateral cancers. Cases had a significantly 3-fold higher excess of familial breast cancer than did controls (cases: O/E = 2.65, 95% CI = 1.85–3.69; controls: 0.86, 0.46–1.47; homogeneity: p = 0.00). Risk did not vary with menopausal status of the patient, but was greatest if a relative was diagnosed before age 45 (O/E = 38.9; 95% CI = 21.7–64.1). By implication, young first-degree relatives of patients with bilateral breast cancer are at very high risk of breast cancer themselves. Cases also had significantly fewer siblings than did controls. ^ Earlier menarche, and parity in the absence of lactation, were associated with bilateral cancers; age at menopause and parity with lactation were not. A history of alcohol consumption, particularly if heavy, carried a 3.4-fold risk (p = 0.03). The data suggested a slightly different pattern in risk factors according to menopausal status and interval between cancers. ^ Replication error phenotype was available for 59 probands. It was associated with bilateral cancers (particularly if diagnosed within one year of each other), increased age (p = 0.02) and negative nodal status. Invasive lobular histology was associated with bilateral disease but numbers were small. ^ These data suggest bilateral breast cancer arises in the context of a combination of familial and hormonal factors, and alcohol consumption. The relative importance of each factor may vary by age of the patient. ^

Familial component of epilepsy in cleft lip and palate

It is well recognized that offspring of women with epilepsy who are taking anticonvulsant medications have an increased incidence of clefting abnormalities. This increase has been attributed to the teratogenic effects of anticonvulsant medications but an alternative explanation involving a genetic association of epilepsy and clefting has also been proposed. Five family studies attempting to resolve this controversy have been inconclusive either because of study design or analytic limitations. This family study was designed to determine whether epilepsy aggregates in families ascertained by an individual with a clefting disorder. The Mayo Clinic medical linkage registry was used to identify individuals with cleft lip with or without cleft palate and cleft palate in southeast Minnesota from 1935-1986. Only those cases who were 15 years or younger during this period were included in the study. The proband's parents and descendants of their parents, including the proband's sibs, children, grandchildren, niece/nephews, grandnieces/nephews, halfsibs and spouses were also identified and all of their medical records were reviewed for seizure disorders. The standardized morbidity ratios for epilepsy of 0.9 (95% CI 0.2-2.6) observed for first degree relatives (excluding parents) and 0.0 for second degree relatives were not increased. The SMRs ranged from 0.7-2.2 for the individual relative types (parents 1.5, sibs 0.7, children 2.2, probands 1.1, spouses 2.0) and were also not increased. These results do not support the suggestions of some that clefting and epilepsy aggregate together in families. ^

Genetic epidemiology of childhood brain tumors

A rare familial cancer syndrome involving childhood brain tumors (CBT), breast cancer, sarcomas and an array of other tumors has been described (Li and Fraumeni 1969, 1975, 1982, 1987). A survey of CBT identified through the Connnecticut Tumor Registry in 1984 revealed a high frequency of CBT, leukemia and other childhood cancer in siblings of CBT patients (Farwell and Flannery, 1984). Other syndromes such as neurofibromatosis and nevoid basal cell carcinoma syndrome have also been associated with CBT; however, no systematic family studies have been conducted to determine the extent to which cancer aggregates in family members of CBT patients. This family study was designed to determine the frequency of cancer aggregation overall or at specific sites, to determine the frequency of known or potentially hereditary syndromes in families of CBT patients, and to determine a genetic model to characterize familial cancer syndromes and to identify specific kindreds to which such a model(s) might apply. This study includes 244 confirmed CBT patients referred to the University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed under the age of 15 years and resident in the U.S. or Canada. Family histories were obtained on the proband's first (parents, siblings and offspring) and second degree (proband's aunts, uncles and grandparents) relatives following sequential sampling scheme rules. To determine if cancer aggregates in families, we compared the cancer experience in the population to that expected in the general population using Connecticut Tumor Registry calendar year, age, race and sex-specific rates. The standardized incidence ratio (SIR) for cancer overall was 0.91 (41 observed (O) and 44.94 expected (E); 95% Confidence Interval (CI) = 0.65-1.24). We observed a significant excess of colon cancer among the proband's first degree relatives (O/E = 5/1.64; 95% CI = 1.01-7.65), in particular those under age 45 year. Segregation analysis showed evidence for multifactorial inheritance in the small percentage (N = 5) of the families. ^

Colorectal cancer screening: Participation and determinants in West Texas

Early detection by screening is the key to colorectal cancer control. However, colorectal cancer screening and its determinants in rural areas have not been adequately studied. This goal of this study was to investigate the screening participation and determinants of colonoscopy, sigmoidoscopy, and/or fecal occult blood test (FOBT) in subjects of Project Frontier from the rural counties of Cochran, Bailey and Parmer, Texas. Subjects ( n=820 with 435 Hispanics, 355 Non-Hispanic Whites, 26 African Americans, and 4 unknown ethnicity; 255 males, 565 females, aged from 40 to 92 years) were from Project FRONTIER. Stepwise logistic regression analysis was performed. Explanatory variables included ethnicity (Hispanic, Non-Hispanic white and African American), gender, health insurance, smoking status, household income, education (years), physical activity, overweight, other health screenings, personal physicians, family history (first-degree relatives) of cancers, and preferred language (English vs. Spanish) for interview/testing. The screening percentage for ever having had a colonoscopy/sigmoidoscopy (51.8%) in this cohort aged 50 years or older is well below the percentage of the nation (65.2%) and Texas (64.6%) while the percentage for FOBT (29.2%) is higher than in the nation (17.2%) and Texas (14.9%). However, Hispanics had significantly lower participation than non-Hispanic whites for colonoscopy/sigmoidoscopy (37.0% vs. 66.0%) and FOBT (16.5% vs. 41.7%), respectively. Stepwise logistic regression showed that predictors for colonoscopy, sigmoidoscopy or FOBT included Hispanic race (p = 0.0045), age (p < 0.0001), other screening procedure (p < 0.0001), insurance status (p < 0.0001) and physician status (p = 0.0053). Screening percentage for colonoscopy/sigmoidoscopy in this rural cohort is well below the national and Texas level mainly due to the lower participation of Hispanics vs. Non-Hispanic whites. Health insurance, having had a personal physician, having had screenings for other cancers, race, and older age are among the main predictors.^

Epidemiology of secondary leukemia with reference to chromosomal abnormalities

Secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been recognized as one of the most feared long-term complications of cancer therapy. The aim of this case-control study was to determine the prevalence of chromosomal abnormalities and family history of cancer among secondary AML/MDS cases and de novo AML/MDS controls. Study population were 332 MD Anderson Cancer Center patients who were registered between 1986 and 1994. Cases were patients who had a prior invasive cancer before diagnoses of AML/MDS and controls were de novo AML/MDS. Cases (166) and controls (166) were frequency matched on age $\pm$5 years, sex and year of diagnosis of leukemia. Cytogenetic data were obtained from the leukemia clinic database of MD Anderson Cancer Center and data on family history of cancer and other risk factors were abstracted from the patients' medical record. The distribution of AML and MDS among cases was 58% and 42% respectively and among controls 67% and 33% respectively. Prevalence of chromosomal abnormalities were observed more frequently among cases than controls. Reporting of family history of cancer were similar among both groups. Univariate analysis revealed an odds ratio (OR) of 2.8 (95% CI 1.5-5.4) for deletion of chromosome 7, 1.9 (95% CI 0.9-3.8) for deletion of chromosome 5, 2.3 (95% CI 0.8-6.2) for deletion of 5q, 2.0 (95% CI 1.0-4.2) for trisomy 8, 1.3 (95% CI 0.8-2.1) for chromosomal abnormalities other than chromosome 5 or 7 and 1.3 (95% CI 0.8-2.0) for family history of cancer in a first degree relative. The OR remained significant for deletion of chromosome 7 (2.3, 95% CI 1.1-4.8) after adjustment for age, alcohol, smoking, occupation related to chemical exposure and family history of cancer in a first degree relative. Of the 166 secondary AML/MDS patients 70% had a prior solid tumor and 30% experienced hematological cancers. The most frequent cancers were breast (21.1%), non-Hodgkin lymphoma (13.3%), Hodgkin's disease (10.2%), prostate (7.2%), colon (6%), multiple myeloma (3.6%) and testes (3.0%). The majority of these cancer patients were treated with chemotherapy or radiotherapy or both. Abnormalities of chromosome 5 or 7 were found to be more frequent in secondary AML/MDS patients with prior hematological cancer than patients with prior solid tumors. Median time to develop secondary AML/MDS was 5 years. However, secondary AML/MDS among patients who received chemotherapy and had a family history of cancer in a first degree relative occurred earlier (median 2.25 $\pm$ 0.9 years) than among patients without such family history (median 5.50 $\pm$ 0.18 years) (p $<$.03). The implication of exposure to chemotherapy among patients with a family history of cancer needs to be further investigated. ^

Relationships between the alterations of tumor suppressor genes, risk factors and clinical outcomes of gliomas

The relationship between MMAC/PTEN, DMBT1 and the progression and prognosis of glioma, and the association between the alterations of MMAC/PTEN, p53, p16, and Rb and some cancer risk factors, such as smoking, exposure to radiation, family cancer history, and previous cancer history, were assessed in 4 studies. ^ By allelic deletion analysis, MMAC/PTEN locus was shown to be frequently lost in glioblastomas multiforme (GM) but maintained in most lower-grade astrocytic tumors. DMBT1 locus, however, was frequently lost in all grades of gliomas examined. The potential biological significance of these two regions was frontier assessed by examining microcell-hybrids that contained various fragments of 10q. Somatic cell hybrid clones that retained the MMAC/PTEN locus have less transformed phenotypes, exhibiting an inability to grow in soft agarose. On the other hand, the presence or absence of DAMT1 did not correlate with any in vitro phenotype assessed in our model system. Further, Cox proportional hazards regression analysis, adjusted for age at surgery and histologic grades (GM, and non-GM), showed that without LOH at the MMAC/PTEN locus had a significantly better prognosis than did patients with LOH at MMAC/ PTEN (hazard ratio = 0.5; 95% Cl = 0.28–0.89; P = 0.018). Furthermore, status of LOH at MMAC/PTEN was found to be significantly associated with age, while that for DMBT1 was not. These results suggest that the DMBT1 may be involved early in the oncogenesis of gliomas, while alterations in the MMAC /PTEN may be a late event in the oncogenesis related with progression of gliomas and provide a significant prognostic marker for patient survival. ^ The associations between 4 cancer risk factors and 4 tumor suppressor genes were assessed. The expression of p16 was observed to be associated with current smoking (adjusted OR = 1.9, 95% CI = 1.02–3.6) but not the former smoking (adjusted OR = 1.1, 95% Cl = 0.5–3.5). The expression of p53 was found to be associated with the family cancer history (OR = 3.5, 95% Cl = 1.07–11 for patients with first-degree family history of cancer). MMAC/ PTEN was associated with the histologic grade (OR = 2.8, 95% CI = 1.2–6.6) and age (P = 0.035). Also, the OR for LOH around MMAC/PTEN in patients with a family history of cancer was elevated (OR = 1.9, 95% CI = 0.8–4.6 for patients with first-degree family history of cancer). The associations between exposure and the alterations of tumor suppressor genes, between smoking and p16, between family history of cancer and p53 and MMAC/PTEN, provide suggestive evidences that those exposures are related to the development of gliomas. ^

Breast cancer risk factors among Mexican-American women

Introduction: The average age of onset of breast cancer among Hispanic women is 50 years, more than a decade earlier than non-Hispanic white women. Age at diagnosis is an important prognostic factor for breast cancer; younger age at onset is more likely to be associated with advanced disease, poorer prognosis, hormone receptor negative breast tumors, and a greater likelihood of hereditary breast cancer. Studies of breast cancer risk factors including reproductive risk factors, family history of breast cancer, and breast cancer subtype have been conducted predominately in non-Hispanic whites. Breast cancer is a heterogeneous disease with the presence of clinically, biologically, and epidemiologically distinct subtypes that also differ with respect to their risk factors. The associations between reproductive risk factors and family history of breast cancer have been well documented in the literature. However, only a few studies have assessed these associations with breast cancer subtype in Hispanic populations. Methods: To assess the associations between reproductive risk factors and family history of breast cancer we conducted three separate studies. First, we conducted a case-control study of 172 Mexican-American breast cancer cases and 344 age matched controls residing in Harris County, TX to assess reproductive and other risk factors. We conducted logistic regression analysis to assess differences in cases and controls adjusted for age at diagnosis and birthplace and then we conducted a multinomial logistic regression analysis to compare reproductive risk factors among the breast tumor subtypes. In a second study, we identified 139 breast cancer patients with a first- or second-degree family history of breast cancer and 298 without a family history from the ELLA Bi-National Breast Cancer Study. In this analysis, we also computed a multinomial logistic regression to evaluate associations between family history of breast cancer and breast cancer subtypes, and logistic regression to estimate associations between breast cancer screening practices with family history of breast cancer. In the final study, we employed a cross-sectional study design in 7279 Mexican-American women in the Mano a Mano Cohort Study. We evaluated associations with family history of breast cancer and breast cancer risk factors including body mass index (BMI), lifestyle factors, migration history, and adherence to American Cancer Society (ACS) guidelines. Results: In the results of our first analyses, reproductive risk factors differed in the magnitude and direction of associations when stratified by age and birthplace among cases and controls. In our second study, family history of breast cancer, and having at least one relative diagnosed at an early age (<50 years) was associated with triple negative breast cancer (TNBC). Mammography prior to receiving a breast cancer diagnosis was associated with family history of breast cancer. In our third study that assessed lifestyle factors, migration history and family history of breast cancer; we found that women with a first-degree family history of breast cancer were more overweight or obese compared with their counterparts without a family history. There was no indication that having a family history contributed to women practicing healthier lifestyle behaviors and/or adhering to the ACS guidelines for cancer prevention. Conclusions: We observed that among Mexican-American women, reproductive risk factors were associated with breast cancer where the woman was born (US or Mexico). Having a family history of breast cancer, especially having either a first- or second-degree relative diagnosed at a younger age, was strongly associated with TNBC subtype. These results are consistent with other published studies in this area. Further, our results indicate that women with strong family histories of breast cancer are more likely to undertake mammography but not to engage in healthier lifestyle behaviors.^

THE RELATIONSHIP BETWEEN DEGREE OF BLOOD PRESSURE REDUCTION AND MORTALITY AMONG HYPERTENSIVES IN THE HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM

The relationship between degree of diastolic blood pressure (DBP) reduction and mortality was examined among hypertensives, ages 30-69, in the Hypertension Detection and Follow-up Program (HDFP). The HDFP was a multi-center community-based trial, which followed 10,940 hypertensive participants for five years. One-year survival was required for inclusion in this investigation since the one-year annual visit was the first occasion where change in blood pressure could be measured on all participants. During the subsequent four years of follow-up on 10,052 participants, 568 deaths occurred. For levels of change in DBP and for categories of variables related to mortality, the crude mortality rate was calculated. Time-dependent life tables were also calculated so as to utilize available blood pressure data over time. In addition, the Cox life table regression model, extended to take into account both time-constant and time-dependent covariates, was used to examine the relationship change in blood pressure over time and mortality.^ The results of the time-dependent life table and time-dependent Cox life table regression analyses supported the existence of a quadratic function which modeled the relationship between DBP reduction and mortality, even after adjusting for other risk factors. The minimum mortality hazard ratio, based on a particular model, occurred at a DBP reduction of 22.6 mm Hg (standard error = 10.6) in the whole population and 8.5 mm Hg (standard error = 4.6) in the baseline DBP stratum 90-104. After this reduction, there was a small increase in the risk of death. There was not evidence of the quadratic function after fitting the same model using systolic blood pressure. Methodologic issues involved in studying a particular degree of blood pressure reduction were considered. The confidence interval around the change corresponding to the minimum hazard ratio was wide and the obtained blood pressure level should not be interpreted as a goal for treatment. Blood pressure reduction was attributed, not only to pharmacologic therapy, but also to regression to the mean, and to other unknown factors unrelated to treatment. Therefore, the surprising results of this study do not provide direct implications for treatment, but strongly suggest replication in other populations. ^