Sir Peter MacCallum Department of Oncology - Research Publications
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ItemCopy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers(NATURE PORTFOLIO, 2022-10-06)The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
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ItemThe Clinical and Psychosocial Outcomes for Women Who Received Unexpected Clinically Actionable Germline Information Identified through Research: An Exploratory Sequential Mixed-Methods Comparative Study(MDPI, 2022-07)Background Research identifying and returning clinically actionable germline variants offer a new avenue of access to genetic information. The psychosocial and clinical outcomes for women who have received this ‘genome-first care’ delivering hereditary breast and ovarian cancer risk information outside of clinical genetics services are unknown. Methods: An exploratory sequential mixed-methods case-control study compared outcomes between women who did (cases; group 1) and did not (controls; group 2) receive clinically actionable genetic information from a research cohort in Victoria, Australia. Participants completed an online survey examining cancer risk perception and worry, and group 1 also completed distress and adaptation measures. Group 1 participants subsequently completed a semi structured interview. Results: Forty-five participants (group 1) and 96 (group 2) completed the online survey, and 31 group 1 participants were interviewed. There were no demographic differences between groups 1 and 2, although more of group 1 participants had children (p = 0.03). Group 1 reported significantly higher breast cancer risk perception (p < 0.001) compared to group 2, and higher cancer worry than group 2 (p < 0.001). Some group 1 participants described how receiving their genetic information heightened their cancer risk perception and exacerbated their cancer worry while waiting for risk-reducing surgery. Group 1 participants reported a MICRA mean score of 27.4 (SD 11.8, range 9−56; possible range 0−95), and an adaptation score of 2.9 (SD = 1.1). Conclusion: There were no adverse psychological outcomes amongst women who received clinically actionable germline information through a model of ‘genome-first’ care compared to those who did not. These findings support the return of clinically actionable research results to research participants.
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ItemMendelian randomisation study of smoking exposure in relation to breast cancer risk(SPRINGERNATURE, 2021-10-12)BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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ItemBreast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores(OXFORD UNIV PRESS INC, 2022-01)BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
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ItemEvaluation of two population screening programmes for BRCA1/2 founder mutations in the Australian Jewish community: a protocol paper(BMJ PUBLISHING GROUP, 2021)INTRODUCTION: People of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a BRCA1/2 pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific BRCA1/2 pathogenic variants, referred to as BRCA-Jewish founder mutations (B-JFM), account for >90% of BRCA1/2 pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for BRCA testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants. Here we describe the protocol of the JeneScreen study-a study established to develop and evaluate two different population-based B-JFM screening programmes, offered to people of Jewish ancestry in Sydney and Melbourne, Australia. METHODS AND ANALYSIS: To rmeasure the acceptability of population-based B-JFM screening in Australia, two screening programmes using different methodologies have been developed. The Sydney JeneScreen programme provides information and obtains informed consent by way of an online tool. The Melbourne JeneScreen programme does this by way of community sessions attended in person. Participants complete questionnaires to measure clinical and psychosocial outcomes at baseline, and for those who have testing, 2 weeks postresult. Participants who decline testing are sent a questionnaire regarding reasons for declining. Participants with a B-JFM are sent questionnaires 12-month and 24-month post-testing. The questionnaires incorporate validated scales, which measure anxiety, decisional conflict and regret, and test-related distress and positive experiences, and other items specifically developed or adapted for the study. These measures will be assessed for each programme and the two population-based B-JFM screening methods will be compared. ETHICS AND DISSEMINATION: Institutional Human Research Ethics Committee approval was obtained from the South Eastern Area Health Service Human Research Ethics Committee: HREC Ref 16/125.Following the analysis of the study results, the findings will be disseminated widely through conferences and publications, and directly to participants in writing.
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ItemInvestigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study(NATURE RESEARCH, 2021-06-11)Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon-intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10-9) and missense (OR 1.27, p = 3.96 × 10-73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2-4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
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ItemMutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations(WILEY-HINDAWI, 2018-05)The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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ItemCYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers(SPRINGERNATURE, 2021-02-16)BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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ItemExome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles(PUBLIC LIBRARY SCIENCE, 2012-09)Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.
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ItemPrevalence of PALB2 mutations in Australian familial breast cancer cases and controls(BMC, 2015-08-19)INTRODUCTION: PALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. However, large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing. METHODS: In this study we analyse almost 2000 breast cancer cases sourced from individuals referred to familial cancer clinics, thus representing typical cases presenting in clinical practice. These cases were compared to a similar number of population-based cancer-free controls. RESULTS: We identified a significant excess of truncating variants in cases (1.3 %) versus controls (0.2 %), including six novel variants (p = 0.0001; odds ratio (OR) 6.58, 95 % confidence interval (CI) 2.3-18.9). Three of the four control individuals carrying truncating variants had at least one relative with breast cancer. There was no excess of missense variants in cases overall, but the common c.1676A > G variant (rs152451) was significantly enriched in cases and may represent a low-penetrance polymorphism (p = 0.002; OR 1.24 (95 % CI 1.09-1.47). CONCLUSIONS: Our findings support truncating variants in PALB2 as high-penetrance breast cancer susceptibility alleles, and suggest that a common missense variant may also lead to a low level of increased breast cancer risk.