Analgesic use and the risk of renal cell carcinoma - Findings from the Consortium for the Investigation of Renal Malignancies (CONFIRM) study.

PURPOSE: The incidence of renal cell carcinoma (RCC) is rising. Use of analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol may affect renal function. The aim of this study was to assess associations between analgesic use and risk of RCC. METHODS: A population-based case-control family design was used. Cases were recruited via two Australian state cancer registries. Controls were siblings or partners of cases. Analgesic use was captured by self-completed questionnaire. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for RCC risk associated with regular analgesic use (at least 5 times per month for 6 months or more) and duration and frequency of use. RESULTS: The analysis included 1064 cases and 724 controls. Regular use of paracetamol was associated with an increased risk of RCC (OR 1.41, 95%CI 1.13-1.77). Regular use of NSAIDs was associated with increased risk of RCC for women (OR 1.71, 95% CI 1.23-2.39) but not men (OR 0.83, 95% CI 0.58-1.18; p-interaction=0.003). There was no evidence of a dose-response for duration of use of paracetamol (linear trend p = 0.77) and weak evidence for non- aspirin NSAID use by women (linear trend p = 0.054). CONCLUSION: This study found that regular use of paracetamol was associated with increased risk of RCC. NSAID use was associated with increased risk only for women.

Evolving Practice Pattern of Palliative Radiation Therapy for Bone Metastases from Lung Cancer in Australia.

AIMS: Radiation therapy is an effective treatment for bone metastases. Single-fraction conformal radiation therapy (SF-CRT) is equally effective as multifraction radiation therapy for the management of uncomplicated bone metastases. There has been a rapid development of advanced radiation therapy techniques (ART) in radiation oncology. We evaluated the changing pattern of SF-CRT and ART use for the management of bone metastases in lung cancer. MATERIALS AND METHODS: This was a state-wide population-based cohort of lung cancer patients from Victoria, Australia, who received radiation therapy for bone metastases between 2012 and 2017. The primary outcomes were proportion of radiation therapy courses using: SF-CRT and ART. We identified a subcohort in which radiation therapy was delivered at the end of life (EOL), i.e. within 30 days of death. The Cochran-Armitage test for trend was used to evaluate the change in pattern of SF-CRT and ART use over time. Multivariable analyses were used to identify factors associated with the primary outcomes. RESULTS: Of the 4335 courses of radiation therapy for bone metastases in lung cancer, 20% were SF-CRT - increasing from 19% in 2012 to 26% in 2017 (P-trend = 0.004). In multivariate analyses, treatment to the rib, shoulder, hip or extremities, and treatment in public institutions were independently associated with SF-CRT use, but the effect of year of radiation therapy was no longer significant. Five per cent of radiation therapy was delivered using ART, increasing markedly from 2016 onwards (P-trend < 0.001). In multivariate analyses, treatment in private institutions and more recent years of treatment were independently associated with the use of ART. There were 587 courses of radiation therapy delivered at the EOL, with SF-CRT more commonly used closer to death - 53%, 29% and 25% of radiation therapy within 7 days, 8-14 days and 15-30 days of death, respectively. CONCLUSION: SF-CRT continued to be underutilised for bone metastases in lung cancer in Australia, including at the EOL. We observed an increase in ART use for bone metastases from 2016, which occurred contemporaneously with changes in government funding.

Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Hospital lung surgery volume and patient outcomes.

OBJECTIVES: There has been evidence of an association between patient outcomes and the number of surgeries performed at a hospital. To our knowledge, there are no Australian data on hospital cancer surgery volumes and patient outcomes. We evaluated the relationship between hospital non-small cell lung cancer (NSCLC) surgery volume and patient outcomes in Victoria. MATERIALS AND METHODS: Patients with a primary diagnosis of NSCLC between 2008 and 2014 were identified in the Victorian Cancer Registry (n = 15,369), 3,420 (22%) of whom had lung cancer surgery. Primary outcome was death within 90 days of surgery and secondary outcomes included overall survival, use of postoperative ventilation and ≥24hours spent in ICU. Hospital volume was measured as the average number of lung surgeries performed per year, with quartiles Q1: 1-17, Q2: 18-34, Q3: 35-58 and Q4: 59 + . RESULTS: 57% (1,941/3,420) lung cancer patients underwent lobectomy, 38% (1,299/3,420) sub-lobar resection and 5% (180/3,420) pneumonectomy. The overall 90-day mortality after lung surgery was 3.5%, and was 2.6% and 4.5% for patients undergoing lobectomy and sub-lobar resection respectively. There was no difference in 90-day mortality and overall survival between low- and high-volume centres regardless of procedure. Patients operated on in lower volume centres had more admissions to ICU ≥24hours (Q1. 55% vs. Q4. 11%, p-trend <0.001). A higher proportion of patients attending private hospitals (19%) had an ASA score of 4 compared with patients attending a public hospital (9%). CONCLUSION: We observed no evidence of survival differences between lung cancer patients attending low- and high-volume hospitals for cancer surgery. A higher proportion of patients had an ICU admission ≥24hours in lower volume centres and there are a higher proportion of patients with an ASA score of 4 in private hospitals compared to public hospitals.

Dietary inflammatory index or Mediterranean diet score as risk factors for total and cardiovascular mortality.

BACKGROUND AND AIMS: Dietary patterns are associated with risk of cardiovascular disease (CVD). We aimed to examine associations of the Dietary Inflammatory Index (DII) and the Mediterranean Diet Score (MDS) with total, cardiovascular disease (CVD) and coronary heart disease (CHD) mortality in the Melbourne Collaborative Cohort Study; and compare the strengths of the associations. METHODS AND RESULTS: In our prospective cohort study of 41,513 men and women aged 40-69 years, a food frequency questionnaire was completed at baseline and mortality data were obtained via linkage with local and national registries over an average of 19 years follow up. At baseline, questionnaires were completed and physical measures and blood samples taken. Cox proportional hazards models, adjusting for age, alcohol consumption, sex, region of origin, personal history of CVD or diabetes and family history of CVD, were used to assess associations between dietary scores and mortality. More Mediterranean or less inflammatory diets were associated with lower total, CVD and CHD mortality. The hazard ratio for total mortality comparing the highest and lowest quintiles was 1.16 (95%CI: 1.08-1.24) for DII; and 0.86 (95%CI: 0.80-0.93) comparing the highest and lowest three categories of MDS. Using the Bayesian information criterion, there was no evidence that the DII score was more strongly associated with total and CVD mortality than was the MDS. CONCLUSIONS: The MDI and the DII show similar associations with total and cardiovascular mortality, consistent with the consensus that plant-based diets are beneficial for health.

Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Whether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery. AIM: This multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population. METHODS: Eligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three-yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia. RESULTS: Of 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45; 95% confidence interval [CI]: 0.80-5.72; P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87; 95% CI: 0.59-8.43; P = 0.18) and 0.99 expected (SIR = 2.01; 95% CI: 0.24-7.30; P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I-II disease. No serous uterine cancers were reported. CONCLUSIONS: Our findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers.

Improved quality of risk-reducing salpingo-oophorectomy in Australasian women at high risk of pelvic serous cancer.

OBJECTIVES: The quality of risk-reducing salpingo-oophorectomy (RRSO) performed in Australasian women was previously reported to be suboptimal. Here we describe the quality of RRSO performed since 2008 in women enrolled in the same cohort and determine whether it has improved. DESIGN: Prospective cohort study of women at high risk of pelvic serous cancer (PSC) in kConFab. Eligible women had RRSO between 2008 and 2014 and their RRSO surgical and pathology reports were reviewed. "Adequate" surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Associations between clinical factors and "adequate" pathology were assessed using logistic regression. Data were compared with published cohort data on RRSO performed prior to 2008 using Chi square test. RESULTS: Of 164 contemporary RRSOs performed in 78 centres, 158/159 (99%) had "adequate" surgery and 108/164 (66%) had "adequate" pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist [OR 8.2, 95%CI (3.6-20.4), p < 0.001], surgery without concurrent hysterectomy [OR 2.5, 95%CI (1.1-6.0), p = 0.03], more recent year of surgery [OR 1.4, 95%CI (1.1-1.8), p = 0.02], and clinical notation that indicated high risk [OR 19.4, 95%CI (3.1-385), p = 0.008] were independently associated with "adequate" pathology. Both surgery and pathology were significantly more likely to be "adequate" (p < 0.001) in this contemporary sample. CONCLUSION: The quality of RRSOs has significantly improved since our last report. Surgery by a gynaecologic oncologist who informs the pathologist that the woman is at high risk for PSC is associated with optimal RRSO pathology.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families.

Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Adequacy of risk-reducing gynaecologic surgery in BRCA1 or BRCA2 mutation carriers and other women at high risk of pelvic serous cancer.

The aim of this study was to describe the type of risk-reducing gynaecologic surgery (RRGS) and the extent of pathological evaluation being undertaken for Australasian women at high familial risk of pelvic serous cancer. Surgical and pathology reports were reviewed for women with BRCA1/BRCA2 mutations, or a family history of breast and ovarian cancer, who underwent RRGS between 1998 and 2008. "Adequate" surgery was defined as complete removal of all ovarian and extra-uterine fallopian tube tissue. "Adequate" pathology was defined as paraffin embedding of all removed ovarian and tubal tissue. Predictors of adequacy were assessed using logistic regression. There were 201 women, including 173 mutation carriers, who underwent RRGS. Of these, 91% had adequate surgery and 23% had adequate pathology. Independent predictors of adequate surgery were surgeon type (OR = 20; 95% CI 2-167; P = 0.005 for gynaecologic oncologists versus general gynaecologists), more recent surgery (OR = 1.33/year; 95% CI 1.07-1.67; P = 0.012) and younger patient age (OR = 0.93/year of age; 95% CI 0.87-0.99; P = 0.028). Independent predictors of adequate pathology were more recent surgery (OR = 1.26/year; 95% CI 1.06-1.49; P = 0.008) and surgeon type (OR = 3.1; 95% CI 1.4-6.7; P = 0.004 for gynaecologic oncologists versus general gynaecologists). Four serous ovarian cancers and one endometrioid endometrial cancer were detected during surgery or pathological examination. In conclusion Australasian women attending a specialist gynaecologic oncologist for RRGS are most likely to have adequate surgery and pathological examination. Additional education of clinicians and consumers is needed to ensure optimal surgery and pathology in these women.

Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers.

Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS.

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.

Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele)=0.55; 95% confidence interval (CI)=0.34-0.89; P=0.014 and HR (per allele)=0.51; 95%CI=0.30-0.86; and P=0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele)=1.72; 95%CI=1.05-2.82; and P=0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR=1.64 (95% CI=1.26-2.14; P=0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

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.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.