Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees. Australian Breast Cancer Family Study.

Mutations in BRCA1 (ref. 1) confer an increased risk of female breast cancer. In a genome-wide scan of linkage disequilibrium (LD), a high level of LD was detected among microsatellite markers flanking BRCA1 (ref. 3), raising the prospect that positive natural selection may have acted on this gene. We have used the predictions of evolutionary genetic theory to investigate this further. Using phylogeny-based maximum likelihood analysis of the BRCA1 sequences from primates and other mammals, we found that the ratios of replacement to silent nucleotide substitutions on the human and chimpanzee lineages were not different from one another (P=0.8), were different from those of other primate lineages (P=0.004) and were greater than 1 (P=0.04). This is consistent with the historic occurrence of positive darwinian selection pressure on the BRCA1 protein in the human and chimpanzee lineages. Analysis of genetic variation in a sample of female Australians of Northern European origin showed evidence for Hardy-Weinberg (HW) disequilibrium at polymorphic sites in BRCA1, consistent with the possibility that natural selection is affecting genotype frequencies in modern Europeans. The clustering of between-species variation in the region of the gene encoding the RAD51-interaction domain of BRCA1 suggests the maintenance of genomic integrity as a possible target of selection.

Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population-based study.

Women diagnosed with breast cancer before the age of 40 years who have a strong family history of breast and/or ovarian cancer were selected from an Australian population-based case-control-family study for large deletion screening within the BRCA1 promoter. Deletions within the BRCA1 promoter region are usually not detected by the methods applied in routine clinical mutation detection strategies. Fifty-one of the 66 women (77%) who met our inclusion criteria were tested for promoter deletions using linkage disequilibrium analysis of two BRCA1 polymorphic sites (C/G1802 and Pro871Leu) and multiplex ligation-dependent probe amplification. Two cases of BRCA1 promoter deletion involving exons 1A-2 and exons 1A-23 were detected. The morphology of the breast cancers arising in these women with BRCA1 promoter deletions was consistent with the morphology associated with other germline BRCA1 mutations. Large genomic deletions that involve the promoter regions of BRCA1 make up 20% (2/10) of all known BRCA1 mutations in this group of young women with a strong family history of breast and ovarian cancer. Our data support the inclusion of testing for large genomic alterations in the BRCA1 promoter region in routine clinical mutation detection within BRCA1.

Estrogen receptor polymorphism at codon 325 and risk of breast cancer in women before age forty.

BACKGROUND: The estrogen receptor (ER) protein is believed to play a role in the development and progression of breast cancer. In a previously published U.S. clinic-based study, a polymorphism in the ER gene (codon 325, CCC --> CCG) was found to be more common in 34 case subjects with a family history of breast cancer than in 154 case subjects without such a history (mean allele frequencies +/- standard error = 0.28+/-0.05 versus 0.11+/-0.02; P<.001). To determine whether this polymorphism is a risk factor for early-onset breast cancer, we conducted a population-based, case-control-family study in Australia. METHODS: Case subjects under the age of 40 years with a first primary breast cancer and control subjects, frequency-matched to the case subjects on the basis of age, and their relatives were interviewed to assess the family history of breast cancer. Polymorphism status of the ER gene was determined for 388 case subjects and 294 control subjects. All statistical tests were two-tailed. RESULTS: There was no association between ER gene polymorphism status and breast cancer, before or after adjustment for risk factors. There was no difference in allele frequencies between case subjects and control subjects (0.232+/-0.015 versus 0.209+/-0.017; P = .4) or between women with and without a family history of breast cancer (P = .3), irrespective of case-control status. The findings were not altered when different definitions of family history of breast cancer were used and when allele frequencies were adjusted for residence and country of birth. CONCLUSION: We found no evidence that the ER codon 325 polymorphism is associated with breast cancer before the age of 40 years or with a family history of breast cancer, despite ample power to detect effects half the magnitude of those previously reported.

HRAS1 rare minisatellite alleles and breast cancer in Australian women under age forty years.

BACKGROUND: A recent meta-analysis of 23 studies supported the empirically derived hypothesis that women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of breast cancer. These studies relied on visual sizing of alleles on electrophoretic gels and may have underreported rare alleles. We determined whether this hypothesis applied to early-onset breast cancer by using a new method to size minisatellite alleles. METHODS: We conducted a population-based, case-control-family study of 249 Australian women under 40 years old at diagnosis of a first primary breast cancer and 234 randomly selected women, frequency matched for age. We sized HRAS1 minisatellite alleles with an Applied Biosystems model 373 automated DNA sequencer and GENESCAN(TM) software. All P values are two-sided. RESULTS: We found no association of rare alleles with breast cancer, before or after adjustment for risk factors and irrespective of how their effects were modeled (crude odds ratio = 1.04; 95% confidence interval [CI] = 0.071-1.53; P =.8). The rare allele frequency was 0. 173 (95% CI = 0.149-0.197), three times the pooled estimate of 0.058 (95% CI = 0.050-0.066) from previous studies (P<.001), and was similar for case subjects, 0.177 (95% CI = 0.143-0.221), and control subjects, 0.169 (95% CI = 0.135-0.203) (P =.7). CONCLUSION: There was no support for an association between rare HRAS1 alleles and the risk of early-onset breast cancer, despite 80% power to detect effects of the magnitude of those associations (1.7-fold) previously suggested. IMPLICATIONS: The question of whether cancer risk is associated with rare minisatellite HRAS1 alleles needs to be revisited with the use of new methods that have a greater ability to distinguish rare alleles from similarly sized common alleles.

CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.

BACKGROUND: The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer. METHODS: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed. RESULTS: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years. CONCLUSIONS: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.

Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years.

BACKGROUND: We conducted a population-based, case-control-family study to determine whether androgen receptor (AR) exon 1 polymorphic CAG repeat length (CAGn) was a risk factor for early-onset breast cancer in the Australian population. METHODS: Case subjects under 40 years of age at diagnosis of a first primary breast cancer and age-matched control subjects were interviewed to assess family history and other risk factors. AR CAGn length was determined for 368 case subjects and 284 control subjects. Distributions in the two groups were compared by linear and logistic regression, allowing adjustment for measured risk factors. All statistical tests were two-tailed. RESULTS: When analyzed as either a continuous or a dichotomous variable, there was no association between CAG, length and breast cancer risk, before or after adjustment for risk factors. Mean (95% confidence interval [CI]) CAGn lengths were 22.0 (21.8-22.2) for case subjects and 22.0 (21.7-22.3) for control subjects (P = .9). The frequency (95% CI) of alleles with 22 or more CAGn repeats was 0.531 (0.494-0.568) for case subjects and 0.507 (0.465-0.549) for control subjects (P = .4). After adjustment, the average effect on log OR (odds ratio) per allele was 0.16 (95% CI = -0.03 to 0.40; P = .2), and the effect of any allele was equivalent to an OR of 1.40 (95% CI = 0.94-2.09; P = .1). Stratification by family history also failed to reveal any association. Similar results were obtained when alleles were defined by other cutoff points. CONCLUSION: We found no evidence for an association between AR exon 1 CAGn length and breast cancer risk in women under the age of 40, despite having 80% power to detect modest effects.

Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study.

Breast cancers arising in women with and without a germline mutation in the BRCA1 or BRCA2 gene display different histological features, which suggests unique mechanisms of molecular pathogenesis: We used a molecular pathological analysis to define the genetic abnormalities relevant to these specific pathogeneses. Tumor material was studied from 40 women with breast cancer diagnosed before 40 years of age, sampled from a population-based study and stratified by BRCA1 and BRCA2 germline mutation status. Cases were not selected for family history or ethnic origin, and none were known to be genetically related. Thus, germline mutation itself is likely to impact on the molecular pathogenesis of these tumors, with no substantial influence due to modifying genetic or environmental factors. Breast cancers occurring in BRCA1 mutation carriers had significantly higher levels of p53 expression, including the preinvasive (carcinoma in situ) stage of disease, compared with cancers occurring in BRCA2 mutation carriers or women with no detectable germline mutation. These cancers also had a higher proliferation rate as measured by Ki-67 antibody. Expression of the prognostic factors c-erbB-2, cyclin D1, and estrogen receptor was significantly less common in BRCA1 mutation carriers. Lower levels of cyclin D1 were also found in cancers from BRCA2 mutation carriers compared with non-mutation carriers. Direct p53 mutation analysis revealed mutations in 18% of all of the early-onset breast cancers within the study and included rare insertion and deletional mutations in cancers from BRCA1 mutation carriers. Our data indicate that a BRCA1 breast cancer phenotype may be recognized by an exceptionally high proliferation rate and early and frequent p53 overexpression but infrequent selection for overexpression of several other prognostic factor proteins known to be involved in breast oncogenesis. In contrast, breast cancers arising in BRCA2 mutation carriers have a more heterogeneous phenotypic profile.

Modifying fluoroscopic views reduces operator radiation exposure during coronary angioplasty.

OBJECTIVES: This three-part study examined the feasibility of reducing operator radiation exposure during coronary angioplasty. BACKGROUND: As case loads and complexity increase, some cardiologists are receiving increasing radiation scatter doses. Techniques to reduce this are therefore becoming more important. METHODS: First, the determinants of the operator dose were assessed by measuring the differences in scatter dose with different camera views. The relative contribution of fluoroscopy as opposed to cine was then quantified. Finally, operators were provided with these data, and subsequent changes in technique were evaluated. RESULTS: Left anterior oblique views resulted in 2.6 to 6.1 times the operator dose of equivalently angled right anterior oblique views. Increasing steepness of the left anterior oblique view also resulted in a progressive increase in operator dose, with left anterior oblique 90 degrees causing eight times the dose of left anterior oblique 30 degrees and three times that of left anterior oblique 60 degrees. In the 45 coronary angioplasty cases prospectively analyzed, fluoroscopy was found to be a greater source of total radiation than cine by a 6.3:1 ratio (range 1.1 to 15.8). Once operators were made aware of the importance of left anterior oblique fluoroscopy, there was a marked reduction in its use. When this was not feasible, there was a reduction in the steepness of the angulation. Left anterior oblique fluoroscopy during angioplasty of the left anterior descending and circumflex coronary arteries was reduced from 40% of total screening time to approximately 5%, and left anterior oblique angulation for fluoroscopy during angioplasty of the right coronary artery decreased from 43.6 degrees (+/- 9.1 degrees) to 29.4 degrees (+/- 2.2 degrees). Success rates (90% vs. 89%) and screening times (19.5 vs. 20.7 min) remained unchanged in 200 coronary angioplasties performed after the study. Average operator radiation dose (measured by radiation badges worn under lead at waist level) was reduced from 32.6 to 14.3 microSv/operator per week despite a slight increase in case load. CONCLUSIONS: Fluoroscopy is the major source of total radiation exposure during coronary angioplasty, with left anterior oblique views providing the highest dose. Modification of views is feasible and will result in significant reduction of operator radiation dose.

Design and analysis issues in a population-based, case-control-family study of the genetic epidemiology of breast cancer and the Co-operative Family Registry for Breast Cancer Studies (CFRBCS).

BACKGROUND: Historically, studies of the "genetic epidemiology" of cancer have used nonsystematically sampled kindreds with numerous cases of cancer across multiple generations. From the epidemiologic viewpoint, it is difficult to extrapolate findings to the population because of the ad hoc ascertainment of these atypical, ill-defined families. Since 1992, we have been conducting a population-based, case-control-family study of breast cancer. METHODS: Families are identified through a single, population-sampled proband, who is either affected or unaffected, making adjustment for ascertainment straightforward. Administered questionnaires and blood samples are sought from cases, controls, and specified sets of relatives. From 1996 through 1999, a further 1200 case families have been recruited as part of the Co-operative Family Registry for Breast Cancer Studies (CFRBCS). Issues relevant to the study design and analysis are discussed. RESULTS: Epidemiologic and genetic findings published to date are summarized. In particular, this population-based study has shown that the so-called "high-risk" families containing multiple cases of breast cancer are not typical of families in the general population in which BRCA1 or BRCA2 mutations are segregating. Most "hereditary" cancers are "sporadic." CONCLUSION: The collection of DNA, as well as data on disease status and risk factors, from population-sampled sets of relatives provides a powerful resource for addressing genetic and environmental determinants of cancer. A population-based multicenter, multidisciplinary enterprise, such as has been developed by the CFRBCS, may become a model for future research in cancer epidemiology, allowing genetic and environmental risk factors to be put into a proper population perspective.

Second primary cancers after cancers of the colon and rectum in New South Wales, Australia, 1972-1991.

Data from the New South Wales Central Cancer Registry for the period 1972-1991 were examined to determine the risk of second primary cancers after an initial invasive cancer of the colon (ICD-9 153) or rectum (ICD-9 154). The expected numbers of cancers were obtained by assuming that subjects experienced the same cancer incidence as prevailed in the corresponding general population and by applying sex-, age-, and calendar-specific rates to the appropriate person-years at risk. The relative risk (RR) of a second primary cancer was taken to be the ratio of observed:expected numbers of second cancers. After colon cancer, there was an excess of cancers of the small intestine in both sexes (RRs of 4.5 and 4.4); prostate (RR = 1.4) and kidney (RR = 1.8) in men; and breast (RR = 1.3), body of uterus (RR = 1.9), ovary (RR = 2.8), and thyroid (RR = 2.7) in women. Lung cancer occurred less frequently in men than expected (RR = 0.7). After rectal cancer, men had increased risks of cancers of the colon (RR = 1.5) and prostate (RR = 1.3) and a reduced risk of pancreatic cancer (RR = 0.3). A reciprocal relationship of increased risk was seen between cancers of the proximal (but not the distal) colon and rectum. Shared luminal risk factors for proximal colon cancer and rectal cancer and three syndromes of hereditary predisposition to colon cancer seem to be the major contributors to second primary cancers in patients with an initial colon cancer. Sources of bias have been considered.

Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study.

The average breast cancer risk for carriers of a germ-line mutation in BRCA1 or BRCA2 (penetrance) has been estimated from the multiple-case families collected by the Breast Cancer Linkage Consortium (BCLC) to be approximately 80% to age 70. However, women now being tested for these mutations do not necessarily have the intense family history of the BCLC families. Testing for protein-truncating mutations in exons 2, 11, and 20 of BRCA1 and exons 10 and 11 of BRCA2 was conducted in a population-based sample of 388 Australian women with breast cancer diagnosed before age 40. Onset of breast cancer was analyzed in the known and potential mutation-carrying first- and second-degree female relatives of cases found to carry a mutation. Of the 18 mutation-carrying cases (9 BRCA1 and 9 BRCA2), only 5 (1 BRCA1 and 4 BRCA2) had at least one affected relative, so family history of breast cancer was not a strong predictor of mutation status in this setting. The risk in mutation carriers was, on average, 9 times the population risk [95% confidence interval (CI), 4-23; P < 0.001]. Penetrance to age 70 was 40% (95% CI, 15-65%), about half that estimated from BCLC families. By extrapolation, approximately 6% (95% CI, 2-20%) of breast cancer before age 40 may be caused by protein-truncating mutations in BRCA1 or BRCA2. Breast cancer risk in BRCA1 or BRCA2 mutation carriers may be modified by other genetic or environmental factors. Genetic counselors may need to take into account the family history of the consultand.

The steroid 5alpha-reductase type II TA repeat polymorphism is not associated with risk of breast or ovarian cancer in Australian women.

The enzyme 5alpha-reductase type II (SRD5A2) converts testosterone to its more active form 5alpha-dihydroxytestosterone. The 3' untranslated region of the gene contains a (TA)(n) length polymorphism. The (TA)(9) allele has been reported to be associated with higher serum prostate-specific antigen levels in breast tumors and lower risk of relapse in breast cancer patients and more recently has also been reported to be linked to the codon 89 valine variant, which is itself associated with higher serum prostate-specific antigen levels in breast tumors and a more favorable breast cancer prognosis. We investigated whether the SRD5A2 (TA)(n) polymorphism was associated with risk of breast or ovarian cancer in Australian women by studying 946 breast cancer cases and 509 age-matched controls, and 544 ovarian cancer cases and 298 controls of similar age distribution. The (TA)(9) allele frequency was similar in breast cancer cases (0.110), breast cancer controls (0.125), ovarian cancer cases (0.106), and ovarian cancer controls (0.117). There was no difference in genotype distribution between breast cancer cases and controls (P = 0.5), ovarian cancer cases and controls (P = 0.7), or between the two control groups (P = 0.9). Genotypes containing at least one (TA)(9) allele were not significantly associated with risk of breast cancer overall (odds ratio, 0.86; 95% confidence interval, 0.67-1.12; P = 0.3) or in women stratified by age, menopausal status, or family history. Similarly, the (TA)(9) allele was not associated with risk of ovarian cancer (odds ratio, 0.87; 95% confidence interval, 0.61-1.23; P = 0.4) or with ovarian tumor behavior (invasive or low malignant potential), histology, stage, or grade. Given that this study had sufficient power to detect altered risks in the order of 1.4- to 1.7-fold, our results suggest that the SRD5A2 (TA)(9) allele is unlikely to be associated with moderate alterations in breast or ovarian cancer risk.

Risk factors for kidney cancer in New South Wales--I. Cigarette smoking.

In a population-based case-control study of kidney cancer in New South Wales, data from structured interviews with 489 cases of renal cell cancer (RCC), 147 cases of renal pelvic cancer (CaRP) diagnosed in 1989 and 1990, and 523 controls from the electoral rolls confirmed an increased risk associated with cigarette smoking in both types of cancer. The risk among current smokers was consistently higher than among ex-smokers, and was nearly twice as great for CaRP than for RCC. Additional information provided by this study includes reduced risks following cessation of smoking within 12 years for CaRP, but only after 25 years for RCC. Starting to smoke before, rather than after, the age of 18 years is linked independently with almost twice the risk for CaRP, but does not affect the risk for RCC. No independent trend was found with number of cigarettes smoked per day.

Cancer incidence in New South Wales, Australia.

In 1972, cancer registration began in New South Wales (NSW), the most populous state in Australia. The operations of the Registry are described. By 1990, approximately 316,000 new cases of cancer had been notified from a population that had increased from 4.6 to 5.8 million. In 1981-1984, the most common sites in men were lung, prostate, colon, melanoma and bladder, and in women, breast, melanoma, colon, lung and unknown primary site. Cancers which, between 1973-1976 and 1981-1984, had increased in reported incidence by more than 25% were pharynx and kidney in both sexes, rectum, testis and melanoma in men, and lung and bladder in women; those decreasing by more than 10% were stomach in both sexes, oesophagus in men and cervix in women. Age-standardised incidence rates for melanoma (27.4 [m] and 23.8 [f] per 100,000 in 1987) and cancer of the renal pelvis in women (1.7 per 100,000 in 1989) are among the highest in the world.

Comparison of nicardipine and propranolol for chronic stable angina pectoris.

In a double-blind, randomized, crossover clinical trial, a new calcium antagonist, nicardipine (90 mg/day in 3 divided doses), was compared with propranolol (120 mg/day in 3 divided doses) in 25 patients with chronic stable angina. The mean weekly frequency of angina episodes decreased from 7.8 +/- 1.2 (+/- standard error of the mean) with placebo to 3.8 +/- 1.2 with nicardipine treatment and 3.5 +/- 1 with propranolol treatment (p less than 0.001). With exercise testing, 5 patients receiving nicardipine and 3 receiving propranolol had no angina or ST-segment changes. Comparing paired samples of both drugs with placebo, significant improvement occurred in exercise duration (nicardipine, 1.3 +/- 0.3 minutes, p less than 0.001; propranolol, 1.0 +/- 0.4 minutes, p less than 0.01), time to onset of angina (nicardipine, 1.5 +/- 0.4 minutes, p less than 0.001; propranolol, 1.5 +/- 0.5 minutes, p less than 0.001), maximal ST-segment changes (nicardipine, 0.7 +/- 0.1 mm, p less than 0.01; propranolol, 0.06 +/- 0.1 mm, p less than 0.01) and time to 1 mm of ST depression (nicardipine, 2.5 +/- 0.4 minutes, p less than 0.01; propranolol, 2.0 +/- 0.3 minutes, p less than 0.01). One patient receiving propranolol and 2 receiving nicardipine withdrew from the study because of transient side effects. Mild side effects occurred in 10 patients receiving propranolol and 5 receiving nicardipine. Nicardipine proved to be safe and effective for patients with chronic stable angina; it had fewer side effects than propranolol in the doses used.

Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.

This report notes the differences in the classification of the primary renal disease (PRD) used in different renal dialysis and transplant registries worldwide. The heterogeneity of coding systems complicates the comparative analysis of end-stage renal disease from different regions. Using data collected over two decades in the United States, Europe, and Australia/New Zealand, we present a method for reorganization of the classes of PRD that allows a straightforward comparison of retrospective data from these registries.

Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases.

Whereas papillary renal cell carcinoma is now established as a subtype of renal cell neoplasia, division of these tumors into 2 distinctive morphotypes has been proposed. Type 1 tumors have cells with scanty pale cytoplasm arranged in a single layer on the basement membrane of papillary cores. In these tumors, psammoma bodies and foamy macrophages are frequently seen, and the tumors frequently express cytokeratin 7. Type 2 tumor cells have pseudostratified nuclei and usually have voluminous eosinophilic cytoplasm. Recent studies have supported this subclassification of papillary renal cell carcinoma by demonstrating differing genotypes for type 1 and 2 tumors. To further study the subclassification of papillary renal carcinoma, we compared clinical features, nuclear grade, stage, tumor growth kinetics, and survival in a series of 50 type 1 and 16 type 2 papillary renal cell carcinomas. Comparison of patient age at presentation, sex, and primary tumor size shows no significant difference between the 2 tumor types. Type 1 tumors were of significantly lower Fuhrman grade (P =.0001) and higher Robson stage (P =.009) than type 2 tumors. There was no significant difference when tumors were staged according to the TNM classification. Assessment of tumor growth kinetics showed significantly different mean silver-staining nucleolar organizer region (AgNOR) scores and Ki-67 indices (AgNOR type 1, 3.83, type 2, 7.24, P =.0001; Ki-67 type 1, 3.17%, type 2, 6.01%, P =.0002). Multivariate analysis showed tumor type (P =.03), presence of metastases (P =.04), AgNOR score (P =.001), and Ki-67 index (P =.03) to be independently associated with survival. These results provide evidence of the clinical utility of dividing papillary renal cell carcinomas into 2 types according to histologic characteristics.

Breast cancer in Maori and non-Maori women.

BACKGROUND: Breast cancer is more common in Maori than in non-Maori women under the age of 40 years and is equally common in older women, despite Maori being generally of lower socioeconomic status and having had a higher fertility rate than non-Maori. METHODS: Data from a nationwide population-based case-control study of breast cancer in New Zealand women aged 25-54 years were used to compare the age-adjusted distribution of reproductive and other risk factors for breast cancer in self-identified Maori and non-Maori women from the control group. Separate analyses also were carried out for women aged 25-39 years and for those aged 40-54 years. The risk of breast cancer according to the proportion of Maori ancestry was estimated using multiple logistic regression simultaneously adjusting for several risk factors. RESULTS: Significant differences were found between self-identified Maori and non-Maori women in the age-adjusted frequencies for education level, socioeconomic status, age at first full-term pregnancy, parity, and duration of breastfeeding; the profile in all instances suggesting a lower risk of breast cancer for Maori than for non-Maori. There were no significant differences with respect to age at menarche, surgery for benign breast disease or a family history of breast cancer. Significantly more Maori than non-Maori were in the highest quartile of recent body mass index. Women self-identified as Maori has an approximately twofold higher risk of breast cancer than non-Maori women. CONCLUSIONS: Maori have high rates of breast cancer despite having a more favourable profile than non-Maori for most identified risk factors.

PIP: National statistics collected in New Zealand since the mid-1960s have identified higher rates of breast cancer in Maori women under 40 years of age than their non-Maori counterparts, despite their low socioeconomic status and high fertility. Data from a nationwide population-based case-control study of breast cancer in New Zealand women 25-54 years of age were used to compare the age-adjusted distribution of reproductive and other risk factors for breast cancer in self-identified Maori (n = 89) and non-Maori women (n = 1771) from the control group. Compared with women with no Maori ancestors, women 25-39 years old with at least half Maori ancestry had a two-fold higher risk of breast cancer after adjustment for known risk factors (odds ratio, 2.2; 95% confidence interval, 1.2-4.2). However, when data from the control group were analyzed, Maori women had a significantly more favorable profile in terms of breast cancer risk than their non-Maori counterparts in terms of education level, socioeconomic status, age at first full-term pregnancy, parity, and duration of breast feeding. The only exception to this pattern was body mass index. 62.1% of Maori controls 25-54 years old, compared with 23.1% of their non-Maori counterparts, were in the highest quartile of recent body mass index (p 0.001). The excess of breast cancer in young Maori may reflect unknown genetic factors that increase susceptibility.

Cancer epidemiology in migrant populations.

Migrant studies have taken advantage of the wide geographical variation in cancer risk. Cancer rates in migrants, obtained from routinely collected incidence or mortality statistics, are compared with those in the host country and in the country of origin; the rate of change with time since migration (or age at migration) and in subsequent generations is assessed; and the results are interpreted in the light of differences in socio-economic status and the degree of cultural assimilation. Rapid changes in cancer risk following migration imply that life-style or environmental factors are of overriding importance in aetiology. The susceptibility of fair-skinned races to ultraviolet (UV)-associated skin cancers is an example of racial differences based on inherited factors, but the long-term excess or deficit of other cancers in migrants has not yet been attributed definitively to genetic rather than persisting life-style factors. Are there racial differences in metabolism, DNA repair mechanisms or altered expression of oncogenes or tumour suppressor genes? Several genetic polymorphisms affecting the metabolism of known occupational carcinogens or hormonal factors do vary by race. While classical epidemiology has shown that the environment predominates in determining cancer incidence, molecular epidemiology has identified several examples of genetically determined differences between races.