Melbourne School of Population and Global Health - Research Publications
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ItemScreening participation for people at increased risk of colorectal cancer due to family history: a systematic review and meta-analysis(SPRINGER, 2013-09)We conducted a systematic review and a meta-analysis of observational studies to identify and summarise the level of colorectal cancer (CRC) screening participation for people at increased risk due to family history of the disease. Medline, Cinhal, Embase and PsychInfo databases were comprehensively searched between January 1995 and May 2012 to identify relevant articles. To be included, studies had to report on screening for people who had at least one first-degree relative with CRC and no previous personal diagnosis of the disease. Pooled screening participation levels were calculated for each screening modality. Seventeen studies, accounting for a total of 13,269 subjects with a family history of CRC met the inclusion criteria. Seven studies, including a total of 6,901 subjects had a pooled faecal occult blood testing screening participation (at least once) of 25 % (95 % CI 12-38). Five studies including a total of 5,091 subjects had a pooled sigmoidoscopy-based screening participation (at least once) of 16 % (95 % CI 7-27). Seven studies including a total of 9,965 subjects had pooled participation colonoscopy-based screening (at least once) of 40 % (95 % CI 26-54). There was a significant level of screening heterogeneity between studies. This review identified a substantial underuse of CRC screening for people at increased risk of developing the disease. It highlights the potential opportunity that exists for increasing screening participation among this segment of the population and the need to adjust the current CRC screening policies towards that objective.
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ItemHOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)(SPRINGER, 2013-01)Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
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ItemEstimating single nucleotide polymorphism associations using pedigree data: applications to breast cancer(SPRINGERNATURE, 2013-06-25)BACKGROUND: Pedigrees with multiple genotyped family members have been underutilised in breast cancer (BC) genetic-association studies. We developed a pedigree-based analytical framework to characterise single-nucleotide polymorphism (SNP) associations with BC risk using data from 736 BC families ascertained through multiple affected individuals. On average, eight family members had been genotyped for 24 SNPs previously associated with BC. METHODS: Breast cancer incidence was modelled on the basis of SNP effects and residual polygenic effects. Relative risk (RR) estimates were obtained by maximising the retrospective likelihood (RL) of observing the family genotypes conditional on all disease phenotypes. Models were extended to assess parent-of-origin effects (POEs). RESULTS: Thirteen SNPs were significantly associated with BC under the pedigree RL approach. This approach yielded estimates consistent with those from large population-based studies. Logistic regression models ignoring pedigree structure generally gave larger RRs and association P-values. SNP rs3817198 in LSP1, previously shown to exhibit POE, yielded maternal and paternal RR estimates that were similar to those previously reported (paternal RR=1.12 (95% confidence interval (CI): 0.99-1.27), P=0.081, one-sided P=0.04; maternal RR=0.94 (95% CI: 0.84-1.06), P=0.33). No other SNP exhibited POE. CONCLUSION: Our pedigree-based methods provide a valuable and efficient tool for characterising genetic associations with BC risk or other diseases and can complement population-based studies.
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ItemWhole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles(PUBLIC LIBRARY SCIENCE, 2013-02-08)The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.
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ItemPrevalence of PALB2 mutations in Australasian multiple-case breast cancer families(BMC, 2013)INTRODUCTION: Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. METHODS: The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high-resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. RESULTS: The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), 10 missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense-mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods applied. The majority of breast cancers arising in carriers that were available for review were high-grade invasive ductal carcinomas. CONCLUSIONS: About 1.5% (95% CI 0.6to 2.4) of Australasian multiple-case breast cancer families attending clinics are segregating protein-truncating mutations in PALB2, most being PALB2 c.3113G>A, p.Trp1038*. Given the prevalence, breast cancer risk, and tumour grade associated with this mutation, consideration of clinical PALB2 testing is warranted.
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ItemDynamic changes in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers during various murine peripartum states and over time(SPRINGER, 2013-07)Mammographic density (MD) is a strong heritable risk factor for breast cancer, and may decrease with increasing parity. However, the biomolecular basis for MD-associated breast cancer remains unclear, and systemic hormonal effects on MD-associated risk is poorly understood. This study assessed the effect of murine peripartum states on high and low MD tissue maintained in a xenograft model of human MD. Method High and low MD human breast tissues were precisely sampled under radiographic guidance from prophylactic mastectomy specimens of women. The high and low MD tissues were maintained in separate vascularised biochambers in nulliparous or pregnant SCID mice for 4 weeks, or mice undergoing postpartum involution or lactation for three additional weeks. High and low MD biochamber material was harvested for histologic and radiographic comparisons during various murine peripartum states. High and low MD biochamber tissues in nulliparous mice were harvested at different timepoints for histologic and radiographic comparisons. Results High MD biochamber tissues had decreased stromal (p = 0.0027), increased adipose (p = 0.0003) and a trend to increased glandular tissue areas (p = 0.076) after murine postpartum involution. Stromal areas decreased (p = 0.042), while glandular (p = 0.001) and adipose areas (p = 0.009) increased in high MD biochamber tissues during lactation. A difference in radiographic density was observed in high (p = 0.0021) or low MD biochamber tissues (p = 0.004) between nulliparous, pregnant and involution groups. No differences in tissue composition were observed in high or low MD biochamber tissues maintained for different durations, although radiographic density increased over time. Conclusion High MD biochamber tissues had measurable histologic changes after postpartum involution or lactation. Alterations in radiographic density occurred in biochamber tissues between different peripartum states and over time. These findings demonstrate the dynamic nature of the human MD xenograft model, providing a platform for studying the biomolecular basis of MD-associated cancer risk.
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ItemDietary intake of B vitamins and methionine and breast cancer risk(SPRINGER, 2013-08)PURPOSE: We investigated prospectively the relationship between dietary intakes of methionine and B vitamins associated with one-carbon metabolism and breast cancer risk, including modification by age, hormone receptor status and alcohol consumption. Interactions between different B vitamins and methionine were also examined. METHODS: During follow-up of 20,756 women from the Melbourne Collaborative Cohort Study for an average of 16 years, we ascertained 936 incident breast cancers. Dietary intakes were estimated using a 121-item food frequency questionnaire. Hazard ratios (HR) and 95 % confidence intervals were estimated using Cox regression. RESULTS: We found weak evidence for an inverse association between breast cancer risk and riboflavin intake (fourth versus first quartile, HR Q4 vs. Q1 = 0.84 (0.69, 1.01); p linear trend = 0.05) and a positive association for vitamin B12 (HR Q4 vs. Q1 = 1.21 (1.00, 1.46); p linear trend = 0.06). We did not find any significant interactions between alcohol consumption and any of the B vitamins or methionine intake (all p interaction > 0.17) or between methionine or folate intake and any other B vitamins (all p interaction > 0.07). No association varied by tumor hormone receptor status (all p homogeneity > 0.14). CONCLUSIONS: We found weak evidence of an inverse association between breast cancer risk and riboflavin intake and a positive association with vitamin B12.
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ItemThe Interplay between the Effects of Lifetime Asthma, Smoking, and Atopy on Fixed Airflow Obstruction in Middle Age(AMER THORACIC SOC, 2013-01-01)RATIONALE: The contribution by asthma to the development of fixed airflow obstruction (AO) and the nature of its effect combined with active smoking and atopy remain unclear. OBJECTIVES: To investigate the prevalence and relative influence of lifetime asthma, active smoking, and atopy on fixed AO in middle age. METHODS: The population-based Tasmanian Longitudinal Health Study cohort born in 1961 (n = 8,583) and studied with prebronchodilator spirometry in 1968 was retraced (n = 7,312) and resurveyed (n = 5,729 responses) from 2002 to 2005. A sample enriched for asthma and chronic bronchitis underwent a further questionnaire, pre- and post-bronchodilator spirometry (n = 1,389), skin prick testing, lung volumes, and diffusing capacity measurements. Prevalence estimates were reweighted for sampling fractions. Multiple linear and logistic regression were used to assess the relevant associations. MEASUREMENTS AND MAIN RESULTS: Main effects and interactions between lifetime asthma, active smoking, and atopy as they relate to fixed AO were measured. The prevalence of fixed AO was 6.0% (95% confidence interval [CI], 4.5-7.5%). Its association with early-onset current clinical asthma was equivalent to a 33 pack-year history of smoking (odds ratio, 3.7; 95% CI, 1.5-9.3; P = 0.005), compared with a 24 pack-year history for late-onset current clinical asthma (odds ratio, 2.6; 95% CI, 1.03-6.5; P = 0.042). An interaction (multiplicative effect) was present between asthma and active smoking as it relates to the ratio of post-bronchodilator FEV(1)/FVC, but only among those with atopic sensitization. CONCLUSIONS: Active smoking and current clinical asthma both contribute substantially to fixed AO in middle age, especially among those with atopy. The interaction between these factors provides another compelling reason for atopic individuals with current asthma who smoke to quit.
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ItemReply to comment on: 'Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study'(NATURE PUBLISHING GROUP, 2013-02-19)
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ItemNo Preview AvailableExpression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype(ELSEVIER SCIENCE INC, 2013-12)Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.