A common coding variant in CASP8 is associated with breast cancer risk.

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.

A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact.

Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist.

Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies.

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% CI 46-192), and a polygenic standard deviation of 2.01 (95% CI 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes.

Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation.

Non-Hodgkin lymphoma (NHL) incidence is greatly increased after kidney transplantation. NHL risk was investigated in a nationwide cohort of 8164 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry. NHL diagnoses were ascertained using linkage with national cancer registry records. Multivariate Poisson regression was used to compute incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing risk by transplant function, and risk factors for early (< 2 years) and late (>/= 2 years) NHL during the first transplantation. NHL occurred in 133 patients. Incidence was strikingly lower after transplant failure and cessation of immunosuppression than during transplant function (IRR, 0.25; 95% CI, 0.08-0.80; P = .019). Early NHL (n = 27) was associated with Epstein-Barr virus (EBV) seronegativity at transplantation (IRR, 4.66; 95% CI, 2.10-10.36, P < .001) and receipt of T cell-depleting antibodies (IRR, 2.39; 95% CI, 1.08-5.30; P = .031). Late NHL (n = 79) was associated with increasing year of age (IRR, 1.02; 95% CI, 1.01-1.04; P = .006), increasing time since transplantation (P < .001), and current use of calcineurin inhibitors (IRR, 3.13; 95% CI, 1.53-6.39; P = .002). These findings support 2 mechanisms of lymphomagenesis, one predominantly of primary EBV infection in the context of intense immunosuppression, and another of dysregulated lymphoid proliferation in a prolonged immunosuppressed state.

Consequences in women of participating in a study of the natural history of cervical intraepithelial neoplasia 3.

BACKGROUND: A retrospective cohort study was performed in 1063 women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3) (previously termed carcinoma in situ- CIS) in the National Women's Hospital, Auckland, New Zealand. The study describes the clinical management and outcomes for women with CIN3 diagnosed in the decade of 1965-1974, when treatment with curative intent was withheld in an unethical clinical study of the natural history of CIS. A comparison is made with women who were diagnosed earlier (1955-1964) and later (1975-1976). AIMS: The aim of the study is to record the medical encounters, frequency and management of cytological abnormalities and the occurrence of invasive cancers. The medical records, cytology and histopathology were reviewed and data linked with cancer and death registers. RESULTS: Women diagnosed with CIN3 in 1965-1974 (n = 422), compared with those diagnosed earlier (n = 385) or later (n = 256): (i) were less likely to have initial treatment with curative intent (51% vs 95 and 85%, respectively); (ii) had more follow-up biopsies (P < 0.0005); (iii) were more likely to have positive cytology during follow-up (P < 0.005) and positive smears that were not followed within six months by a treatment with curative intent (P < 0.005); and (iv) experienced a higher risk of cancer of the cervix or vaginal vault (RR = 3.3 compared with the first period, 95% CI: 1.7-5.3). Among women diagnosed in 1965-1974, those initially managed by punch or wedge biopsy alone had a cancer risk ten times (95% CI: 3.9-25.7) higher than women initially treated with curative intent. CONCLUSIONS: During the 'clinical study' (1965-1974), women underwent numerous interventions that were aimed to observe rather than treat their condition, and their risk of cancer was substantially increased.

Immunosuppression and other risk factors for lip cancer after kidney transplantation.

Incidence of lip cancer is markedly increased after kidney transplantation. Immunosuppression and other risk factors for lip cancer were investigated in a population-based, nationwide cohort of 8,162 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry (1982-2003). Lip cancer diagnoses were ascertained using probabilistic data linkage with the Australian National Cancer Statistics Clearing House. Standardized incidence ratios were used to compare lip cancer risk by subsite of lip and during periods of transplant function and failure. Risk factors during the first functioning transplant were examined using multivariate Poisson regression. Lip cancer was diagnosed in 203 patients. All cases were of squamous cell origin and mostly (77%) affected the lower vermillion. Cases occurred predominantly during periods of transplant function, with incidence decreasing to pretransplantation level on transplant failure and cessation of immunosuppression. During transplant function, cancer of the lower vermillion was associated with increasing year of age [incidence rate ratio (IRR), 1.03; 95% confidence interval (95% CI), 1.02-1.05], greater time since transplantation (P < 0.001), smoking (IRR, 2.13; 95% CI, 1.12-4.07), and current use of azathioprine (IRR, 2.67; 95% CI, 1.39-5.15) or cyclosporine (IRR, 1.63; 95% CI, 1.00-2.65). Female sex (IRR, 0.29; 95% CI, 0.18-0.46) and non-Australian/New Zealand country of birth (P = 0.006), surrogate indices of reduced exposure to solar UV radiation, were significantly protective. Lip cancer after transplantation is strongly related to the current receipt of immunosuppression. During transplant function, lip cancer risk is associated with the duration of immunosuppression, receipt of specific immunosuppressive agents, and UV exposure.

The pattern of excess cancer in dialysis and transplantation.

BACKGROUND: After transplantation, cancer risk varies from no increase for several common cancers to a many-fold increase for a number of, chiefly virus-associated, cancers. The smaller excess of cancer in dialysis has been less well described, but two studies suggested that impaired immunity might be responsible. METHODS: In a population-based cohort study of 28 855 patients who received renal replacement therapy (RRT), we categorized incident cancers as end-stage kidney disease (ESKD) related, immune deficiency related, not related to immune deficiency, or of uncertain status, according to whether they were, or were not, increased in published reports of cancer in ESKD prior to starting RRT, organ transplantation or human immunodeficiency virus infection. Standardized incidence ratios for, and excess burdens of, cancer were calculated for all persons normally resident in Australia starting treatment by dialysis or renal transplantation from 1982 to 2003. RESULTS: The risk for ESKD-related cancers was increased 4-fold in dialysis and during transplant function. For immune deficiency-related cancers, the increase was 1.5 (95% CI 1.3-1.6) times in dialysis, and 5-fold after transplantation. ESKD- or immune deficiency-related cancers contributed to approximately 90% of the excess burden of cancer, 48% and 36%, respectively, in dialysis, and 10% and 78% after transplantation. The remaining excess malignancy was contributed by cancers whose relationship with ESKD and immune deficiency is not yet certain. CONCLUSIONS: In RRT, the increase in cancer is restricted, largely if not wholly, to cancers with origins in ESKD or related to immune deficiency. For the former, the cancer risk is similar in dialysis and transplantation, but for immune deficiency-related cancers, the relative risk is much greater after transplantation.

Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study.

BACKGROUND: The invasive potential of cervical intraepithelial neoplasia 3 (CIN3; also termed stage 0 carcinoma) has been poorly defined. At the National Women's Hospital, Auckland, New Zealand, treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974 as part of an unethical clinical study. The resulting variation in management allows comparison of the long-term risk of invasive cancer of the cervix in women whose lesion was minimally disturbed with those who had adequate initial treatment followed by conventional management. We aimed to estimate the long-term risk of invasive cancer in these two groups of women. A judicial inquiry referred for independent clinical review in 1988 all women for whom there remained doubt about the adequacy of their management. METHODS: Between February, 2001, and December, 2004, medical records, cytology, and histopathology were reviewed for all women with CIN3 diagnosed between 1955 and 1976, whose treatment was reviewed by judicial inquiry and whose medical records could be located, and linkages were done with cancer and death registers and electoral rolls. To take into account the probability that the CIN3 lesion had been completely removed, we classified adequacy of treatment by type of procedure, presence of CIN3 at the excision margin, and subsequent cytology. The primary outcome was cumulative incidence of invasive cancer of the cervix or vaginal vault. Follow-up continued until death or Dec 31, 2000, whichever came first. Analyses accounted for procedures during follow-up. FINDINGS: 1229 women whose treatment was reviewed by the judicial inquiry in 1987-88 were included. Of these, 48 records (4%) could not be located and 47 women (4%) did not meet the inclusion criteria. At histopathological review, a further 71 (6% of 1134) women were excluded because the review diagnosis was not CIN3. We identified outcomes in the remaining 1063 (86% of 1229) women diagnosed with CIN3 at the hospital in 1955-76. In 143 women managed only by punch or wedge biopsy, cumulative incidence of invasive cancer of the cervix or vaginal vault was 31.3% (95% CI 22.7-42.3) at 30 years, and 50.3% (37.3-64.9) in the subset of 92 such women who had persistent disease within 24 months. However, cancer risk at 30 years was only 0.7% (0.3-1.9) in 593 women whose initial treatment was deemed adequate or probably adequate, and whose treatment for recurrent disease was conventional. INTERPRETATION: This study provides the most valid direct estimates yet available of the rate of progression from CIN3 to invasive cancer. Women with untreated CIN3 are at high risk of cervical cancer, whereas the risk is very low in women treated conventionally throughout.

Predictors of mammographic density: insights gained from a novel regression analysis of a twin study.

Understanding which factors influence mammographically dense and nondense areas is important because percent mammographic density adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index. Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs ages 40 to 70 years. We used a novel regression modeling approach in which each twin's measure of dense and nondense area was regressed against one or both of the twin's and co-twin's covariates. The nature of changes to regression estimates with the inclusion of the twin and/or co-twin's covariates can be evaluated for consistency with causal and/or other models. By causal, we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change. After adjusting for the individual's weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures, which in absolute log cm(2)/kg was thrice stronger for nondense than dense area. After adjusting for weight, later age at menarche, and greater height were associated with greater dense and lesser nondense areas in a manner inconsistent with causality. The associations of dense and nondense areas with parity are consistent with a causal effect and/or within-person confounding. The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and percent mammographic density and possibly breast cancer risk.

Is MSH2 a breast cancer susceptibility gene?

Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA samples from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependent Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene.

A systematic approach to analysing gene-gene interactions: polymorphisms at the microsomal epoxide hydrolase EPHX and glutathione S-transferase GSTM1, GSTT1, and GSTP1 loci and breast cancer risk.

OBJECTIVE: We undertook a case-control study in an Australian Caucasian population-based sample of 1,246 cases and 664 controls to assess the roles of detoxification gene polymorphisms EPHX T>C Tyr(113)His, GSTT1 deletion, GSTM1 deletion, and GSTP1 A>G Ile(105)Val on risk of breast cancer. METHODS: We systematically addressed the main effects and possible gene-gene interactions using unconditional logistic regression to estimate odds ratios (OR) adjusted for potential confounders and using standard model building approaches based on likelihood theory. RESULTS: There was a decreased risk associated with the EPHX CC genotype [OR, 0.60; 95% confidence interval (95% CI), 0.43-0.84; P = 0.003], marginally significant evidence of increased risk with GSTM1 null genotype (OR, 1.21; 95% CI, 1.00-1.47; P = 0.05), but no association with GSTT1 null genotype (OR, 1.12; 95% CI, 0.86-1.45; P = 0.4) or GSTP1 (OR, 0.95; 95% CI, 0.82-1.10; P = 0.5) genotype. The full model with all interactions gave a significantly better fit than a main-effects-only model (P < 0.001), providing evidence for gene-gene interactions. The most parsimonious model included main effects for EPHX, GSTT1, and GSTM1; a two-way interaction between EPHX and GSTM1; and a three-way interaction between EPHX, GSTM1, and GSTT1. Predicted risks were greatest for women carrying deletions of both GSTT1 and GSTM1, with either the EPHX TC genotype (OR, 2.02; 95% CI, 1.19-3.45; P = 0.009) or EPHX CC genotype (OR, 3.54; 95% CI, 1.29-9.72; P = 0.14). CONCLUSION: Detoxification gene polymorphisms may interact with each other to result in small groups of individuals at modestly increased risk. We caution against overinterpretation and suggest that pooling of similarly large studies is needed to clarify the possible role of such complex gene-gene interactions on breast cancer risk. 2007;16(4):769-74).

Heritability of mammographic density, a risk factor for breast cancer.

BACKGROUND: Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30 percent of the age-adjusted variation in the percentage of dense tissue. METHODS: We undertook two studies of twins to determine the proportion of the residual variation in the percentage of density measured by mammography that can be explained by unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. Information on putative determinants of breast density was obtained by questionnaire. Mammograms were digitized, randomly ordered, and read by a blinded investigator. RESULTS: After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in North America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variants attributable to additive genetic factors) accounted for 60 percent of the variation in density (95 percent confidence interval, 54 to 66) in Australian twins, 67 percent (95 percent confidence interval, 59 to 75) in North American twins, and 63 percent (95 percent confidence interval, 59 to 67) in all twins studied. CONCLUSIONS: These results show that the population variation in the percentage of dense tissue on mammography at a given age has high heritability. Because mammographic density is associated with an increased risk of breast cancer, finding the genes responsible for this phenotype could be important for understanding the causes of the disease.

Fuhrman grading is not appropriate for chromophobe renal cell carcinoma.

This study was undertaken to assess the prognostic effectiveness of Fuhrman nuclear grading and the individual components of this grading system, in a series of chromophobe renal cell carcinomas. Eighty-seven cases of chromophobe renal cell carcinoma were investigated. There were 47 males and 40 females, 28 to 78 years of age. The carcinomas ranged from 25 to 180 mm in size and on TNM staging there were 38 stage I, 25 stage II, 22 stage III, and 2 stage IV tumors. Whole tumor Fuhrman grading was grade 1, 6 cases; grade 2, 72 cases; grade 3, 8 cases; and grade 4, 1 case, whereas focal (single high power field) grading was grade 1, 1 case; grade 2, 62 cases; grade 3, 21 cases; and grade 4, 3 cases. On assignment of nucleolar grading using Fuhrman criteria there were 37 grade 1, 44 grade 2, and 4 grade 3 tumors on whole tumor assessment and 3 grade 1, 63 grade 2, and 21 grade 3 tumors on assessment of the high power field showing the greatest degree of nuclear pleomorphism. Measurements of nuclear size showed nuclear area to range from 26.14 to 100.74 microm2, nuclear perimeter from 19.73 to 39.28 microm, and nuclear major axis from 6.49 to 13.21 microm, whereas the ranges of measures of nuclear shape were; shape factor 0.798 to 0.890, compactness 14.260 to 15.843, and feret diameter 5.694 to 11.242. Follow-up ranged from 1 to 150 months and 8 patients died of tumor-related causes 5 to 53 months from diagnosis. On log rank testing against survival, only patient age (P=0.016) and tumor maximum diameter (P=0.0055) were significant, whereas patient sex and TNM stage were not significant. Whole tumor and focal Fuhrman grading, as well as all measures of nucleolar prominence, nuclear size, and nuclear shape showed no significant association with outcome. It is concluded that neither Fuhrman grading, nor any of the components of the Fuhrman grading system, is useful as prognostic indicators for this tumor type.

The evolution of collagen expression in sarcomatoid renal cell carcinoma.

The development of a sarcomatoid morphotype is recognized as an extreme form of dedifferentiation in renal cell carcinoma and is associated with a poor prognosis. Although sarcomatoid renal cell carcinoma shows pronounced spindle cell morphology, clear cell renal cell carcinoma may show early spindle cell change with cellular elongation, and the prognostic significance of this is debated. To determine the relationship between sarcomatoid renal cell carcinoma and clear cell renal cell carcinoma showing early spindle cell change, we have investigated collagen expression using immunohistochemistry in these 2 tumor types. Both sarcomatoid renal cell carcinoma and early spindle cell change tumors showed pericellular interstitial expression of collagen types I and III, whereas sarcomatoid renal cell carcinoma also showed cytoplasmic expression of these collagen types. Expression of these collagen types in typical clear cell renal cell carcinoma was, in occasional cases, limited to faint and patchy staining in a pericellular interstitial distribution. Tumor cells did not stain for collagen type IV in sarcomatoid renal cell carcinoma, early spindle cell change, or typical clear cell renal cell carcinoma. In sarcomatoid renal cell carcinoma, there was diffuse pericellular expression of collagen type V and patchy pericellular expression of collagen type VI, whereas early spindle cell change tumors showed patchy pericellular staining with antibodies to collagen type V. Collagen type VI expression in early spindle cell change was largely confined to the vascular adventitia and areas of scarring, although very occasional foci of faint interstitial staining were also seen. In typical clear cell renal cell carcinoma, staining of collagen types V and VI was limited to the vascular adventitia and foci of desmoplasia, whereas no staining of tumor cell cytoplasm were seen. This study has shown that collagen expression of sarcomatoid renal cell carcinoma differs from that of early spindle cell change and provides validating evidence that these 2 morphotypes should not be considered together for classification purposes.

Agreement between self-reported breast cancer treatment and medical records in a population-based Breast Cancer Family Registry.

PURPOSE: Although self-report data on treatment for breast cancer are collected in some large epidemiologic studies, their accuracy is unknown. METHODS: As part of a population-based Breast Cancer Family Registry, questionnaires on initial breast cancer treatment and subsequent recurrence were mailed to Australian women diagnosed between 1991 and 1998. These self-report data were validated against medical records for 895 women. RESULTS: The median recall period was 3.2 years, mean age at diagnosis was 44 years, and 81% of women had early-stage breast cancer. Agreement between the two data sources was very high for general questions about type of treatment (100%, 99%, 99%, and 94% for surgery, radiotherapy, chemotherapy, hormonal therapy, respectively). For more specific questions about details of each treatment received, agreement was: for radiation therapy, 96% and 99% for radiation to the breast and chest wall, respectively; for surgery, 83%, 97%, and 88% for lumpectomy, mastectomy, and lymph node dissection, respectively; for hormonal therapy, 94% for tamoxifen; and for chemotherapy, range between 76% and 93%. There was 97% agreement about whether there had been a recurrence, and agreement about the location of recurrence was at least 90% for all sites. Agreement regarding stage at diagnosis was 62%, with discrepancies mostly due to women with locoregional disease incorrectly reporting distant spread. CONCLUSION: This self-report questionnaire can be used to collect accurate data on broad categories of initial breast cancer treatment and recurrence, and even for more detailed information on specifics of treatment and site of recurrence.

The heritability of mammographically dense and nondense breast tissue.

BACKGROUND: Percent mammographic density (PMD) is a risk factor for breast cancer. Our previous twin study showed that the heritability of PMD was 63%. This study determined the heritabilities of the components of PMD, the areas of dense and nondense tissue in the mammogram. METHODS: We combined two twin studies comprising 571 monozygous and 380 dizygous twin pairs recruited from Australia and North America. Dense and nondense areas were measured using a computer-assisted method, and information about potential determinants was obtained by questionnaire. Under the assumptions of the classic twin model, we estimated the heritability of the log dense area and log nondense area and the genetic and environmental contributions to the covariance between the two traits, using maximum likelihood theory and the statistical package FISHER. RESULTS: After adjusting for measured determinants, for each of the log dense area and the log nondense area, the monozygous correlations were greater than the dizygous correlations. Heritability was estimated to be 65% (95% confidence interval, 60-70%) for dense area and 66% (95% confidence interval, 61-71%) for nondense area. The correlations (SE) between the two adjusted traits were -0.35 (0.023) in the same individual, -0.26 (0.026) across monozygous pairs, and -0.14 (0.034) across dizygous pairs. CONCLUSION: Genetic factors may play a large role in explaining variation in the mammographic areas of both dense and nondense tissue. About two thirds of the negative correlation between dense and nondense area is explained by the same genetic factors influencing both traits, but in opposite directions.

BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.

BACKGROUND: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. METHODS: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. RESULTS: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. CONCLUSIONS: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma.

This study was undertaken to determine the validity of Fuhrman grading in a series of papillary renal cell carcinomas (PRCCs), to examine the interrelationship and prognostic significance of the individual components of the grading system, and further to determine whether any observed predictive value was independent of other prognostic indicators. Ninety cases of PRCC were studied. Fifty-nine tumors were of type 1 and 31 were of type 2. There were 33 TNM stage 1, 26 stage 2, 18 stage 3, and 12 stage 4 tumors, whereas division of cases according to pT category showed 14 pT1a, 20 pT1b, 25 pT2, 15 pT3a, 4 pT3b, and 11 pT4 tumors. Ten tumors were grade 1, 58 grade 2, and 22 grade 3 when predominant Fuhrman grade was assigned, whereas grading according to the high-power field containing the highest grade (focal grade) showed 40 grade 2, 49 grade 3, and 1 grade 4 tumors. Measurements of nuclear size (area, major axis, perimeter) and shape (shape factor, compactness) were undertaken using image analysis. Nuclear area ranged from 27.63 to 116.39 microM, major axis length 6.70 to 14.06 microM, and nuclear perimeter 20.05 to 41.77 microM. Shape factor ranged from 0.805 to 0.878 and compactness from 14.33 to 15.66. Predominant nucleolar grade using the criteria of the Fuhrman classification was nucleolar grade 1 for 13 tumors, nucleolar grade 2 for 56 tumors, and nucleolar grade 3 for 21 tumors. Focal nucleolar grade based on the high-power field showing the greatest degree of nuclear pleomorphism, was grade 2 for 38 tumors and grade 3 for 52 tumors. pT category, TNM stage, focal Fuhrman grade, and PRCC type were significantly associated with survival. Of the various measures of the components of the Fuhrman classification, only focal nucleolar grade was associated with survival, on univariate analysis. On multivariate analysis, focal nucleolar grade and tumor diameter were independently associated with survival, whereas TNM stage retained significance independent of other parameters. It is concluded that assessment of nucleolar prominence rather than Fuhrman grade is applicable for stratification of tumors within TNM stage or pT category for PRCC and that this should be based upon the high-power field showing the greatest degree of nuclear pleomorphism.

The enigma of hypertensive ESRD: observations on incidence and trends in 18 European, Canadian, and Asian-Pacific populations, 1998 to 2002.

BACKGROUND: Despite improved treatment of hypertension and decreasing rates of stroke and coronary heart disease, the reported incidence of hypertensive end-stage renal disease (ESRD) increased during the 1990s. However, bias, particularly from variations in acceptance into ESRD treatment (ascertainment) and diagnosis (classification), has been a major source of error when comparing ESRD incidences or estimating trends. METHODS: Age-standardized rates were calculated in persons aged 30 to 44, 45 to 64, and 65 to 74 years for 15 countries or regions (separately for the Europid and non-Europid populations of Canada, Australia, and New Zealand), and temporal trends were estimated by means of Poisson regression. For 10 countries or regions, population-based estimates of mean systolic blood pressures and prevalences of hypertension were extracted from published sources. RESULTS: Hypertensive ESRD, comprising ESRD attributed to essential hypertension or renal artery occlusion, was least common in Finland, non-Aboriginal Australians, and non-Polynesian New Zealanders; intermediate in most European and Canadian populations; and most common in Aboriginal Australians and New Zealand Maori and Pacific Island people. Rates correlated with the incidence of all other nondiabetic ESRD, but not with diabetic ESRD or community rates of hypertension. Between 1998 and 2002, hypertensive ESRD did not increase in Northwestern Europe or non-Aboriginal Canadians, although it did so in Australia. CONCLUSION: Despite the likelihood of classification bias, the probability remains of significant variation in incidence of hypertensive ESRD within the group of Europid populations. These between-population differences are not explained by community rates of hypertension or ascertainment bias.

Review of cytologic slides from the national women's hospital, New Zealand, cohort of women with cervical intraepithelial neoplasia 3 diagnosed in 1955-1976.

OBJECTIVE: To review cytologic slides, mostly at least 25 years old, from women attending National Women's Hospital, Auckland, who had been diagnosed histologically with cervical carcinoma in situ in 1955-1976. STUDY DESIGN: Smears comprised all those from the 2 years following diagnosis as well as all subsequent smears for women who developed "microinvasive" or invasive lower genital tract cancer. The Victorian Cytology Service performed the review using the Australian Modified Bethesda System. was 0.97. RESULTS: Nine percent of 4,930 retrieved slides were technically unsatisfactory. Original (Papanicolaou) and review coding were available for 4,477 slides. Using categories of equivalence, smears coded as normal (original, 59.2%; review, 61.4%) or showing possible or definite high grade abnormalities (original, 25.9%; review, 29.6%) were found in similar proportions. The kappa statistic (0.79) indicated a high level of agreement between original and review coding. In comparison with the review, the sensitivity of the original coding in detecting high grade abnormalities was 0.80, while the ability of the original assessment to categorize smears as not high grade (specificity) CONCLUSION: This comprehensive review found nearly all archived cytology slides to be technically satisfactory and the broad diagnostic cytologic categories from earlier periods (apart from benign lesions) to be concordant with those currently used.