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, .

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).

Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study.

Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal. We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer. Germline TP53 mutation status was assessed by DNA sequencing, screening for heterozygous single-nucleotide polymorphisms, and Multiplex Ligation-Dependent Probe Amplification analyses.

Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study.

Objective: To compare cancer incidence in kidney transplant recipients during periods of transplant function (and immunosuppression) and after transplant failure (when immunosuppression is ceased or reduced). Design, setting, and participants Nationwide, population based retrospective cohort study of 8173 Australian kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry who first received a transplant during 1982-2003. Incident cancers were ascertained using linkage with national cancer registry records.

Cutaneous melanoma is related to immune suppression in kidney transplant recipients.

Melanoma incidence is increased after organ transplantation, but there is uncertainty as to why this occurs. Diagnoses of invasive melanoma were ascertained in 8,152 kidney transplant recipients (1982-2003) by linking national Australian population-based registers, the Australia and New Zealand Dialysis and Transplant Registry, and the Australian National Cancer Statistics Clearing House. Incidence rate ratios (IRR) and standardized incidence ratios were used to compare melanoma risk during periods of transplant function and failure.

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.

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.

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.

An international case-control study of maternal diet during pregnancy and childhood brain tumor risk: a histology-specific analysis by food group.

Purpose: Maternal dietary data from an international collaborative case-control study on childhood brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups during pregnancy.

Methods: Nine study centers from seven countries contributed 1218 cases and 2223 controls. Most cases were diagnosed between 1982 and 1992 and ranged in age from 0 to 19 years.

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.

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.

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.

Family cancer history and risk of brain tumors in children: results of the SEARCH international brain tumor study.

Objective: To examine whether childhood brain tumors (CBTs) are associated with a family history of brain tumors or other cancers in an international case-control study.

Methods: Cancers in children's first- and second-degree relatives were ascertained by interview with parents of 620 children with astroglial tumors, 255 with primitive neuroectodermal tumors, 324 with other CBTs, and 2,218 controls from Australia, Canada, France, Israel, Italy, Spain, and the US. These were used with histories of neurofibromatosis or tuberous sclerosis to exclude in subanalyses children with Li-Fraumeni or other hereditary syndromes predisposing to brain tumors.

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.

Trends in incidence of treated end-stage renal disease, overall and by primary renal disease, in persons aged 20-64 years in Europe, Canada and the Asia-Pacific region, 1998-2002.

Aims: To determine if rates of diabetic and non-diabetic end-stage renal disease (ESRD), which had been rising in young and middle-aged adults in all populations up to the mid-1990s, had started to decline, and if so, whether improvement had occurred in respect of each of the principal primary renal diseases causing ESRD.

Methods: Poisson regression of age- and sex-standardized incidence of ESRD for persons aged 20-64 years in 18 populations from Europe, Canada and the Asia-Pacific region, for 1998-2002.

Results: In persons from 12 European descent (Europid) populations combined, there was a small downward trend in all-cause ESRD (-1.

Increased incidence of squamous cell carcinoma of eye after kidney transplantation.

Squamous cell carcinoma (SCC) of the eye occurs at substantially increased rates in individuals with human immunodeficiency virus (HIV) infection, but it has not been reported in individuals with iatrogenic or congenital immune deficiency. In a national, population-based cohort of 10,180 renal transplantation patients from Australia with 86,898 person-years of follow-up, we ascertained primary incident cancers diagnosed in 1982-2003 by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Standardized incidence ratios (SIRs) of cancer were calculated using age-, sex-, calendar year-, and state/territory-specific population cancer incidence rates.

Genome-wide association study identifies novel breast cancer susceptibility loci.

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies.

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 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.

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.

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.