Melbourne School of Population and Global Health - Research Publications
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ItemPopulation-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testingSouthey, MC ; Dowty, JG ; Riaz, M ; Steen, JA ; Renault, A-L ; Tucker, K ; Kirk, J ; James, P ; Winship, I ; Pachter, N ; Poplawski, N ; Grist, S ; Park, DJ ; Pope, BJ ; Mahmood, K ; Hammet, F ; Mahmoodi, M ; Tsimiklis, H ; Theys, D ; Rewse, A ; Willis, A ; Morrow, A ; Speechly, C ; Harris, R ; Sebra, R ; Schadt, E ; Lacaze, P ; McNeil, JJ ; Giles, GG ; Milne, RL ; Hopper, JL ; Nguyen-Dumont, T (NATURE PORTFOLIO, 2021-12-09)Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1-16.2] for BRCA1, 4.0 [1.9-9.1] for BRCA2, 3.4 [1.4-8.4] for ATM and 4.3 [1.0-17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.
ItemIdentification of new breast cancer predisposition genes via whole exome sequencingSouthey, MC ; Park, DJ ; Lesueur, F ; Odefrey, F ; Nguyen-Dumont, T ; Hammet, F ; Neuhausen, SL ; John, EM ; Andrulis, IL ; Chenevix-Trench, G ; Baglietto, L ; Le Calvez-Kelm, F ; Pertesi, M ; Lonie, A ; Pope, B ; Sinilnikova, O ; Tsimiklis, H ; Giles, GG ; Hopper, JL ; Tavtigian, SV ; Goldgar, DE (Springer Science and Business Media LLC, 2012-01)
ItemRare germline genetic variants and risk of aggressive prostate cancerNguyen-Dumont, T ; MacInnis, RJ ; Steen, JA ; Theys, D ; Tsimiklis, H ; Hammet, F ; Mahmoodi, M ; Pope, BJ ; Park, DJ ; Mahmood, K ; Severi, G ; Bolton, D ; Milne, RL ; Giles, GG ; Southey, MC (WILEY, 2020-05-08)Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case-case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with nonaggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with nonaggressive PrCa (two-tailed Fisher's exact tests, P = .28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with nonaggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = .004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = .06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene-panel tests, for which there is currently an insufficient evidence-base for clinical translation in the context of PrCa risk.
ItemIs RNASEL:p.Glu265*a modifier of early-onset breast cancer risk for carriers of high-risk mutations?Nguyen-Dumont, T ; Teo, ZL ; Hammet, F ; Roberge, A ; Mahmoodi, M ; Tsimiklis, H ; Park, DJ ; Pope, BJ ; Lonie, A ; Kapuscinski, MK ; Mahmood, K ; Goldgar, DE ; Giles, GG ; Winship, I ; Hopper, JL ; Southey, MC (BIOMED CENTRAL LTD, 2018-02-08)BACKGROUND: Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. METHODS: In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. RESULTS: RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p < 0.002). Taqman genotyping demonstrated that the allele frequency of RNASEL:p.Glu265* was similar in affected and unaffected Australian women, consistent with other populations. CONCLUSION: Our study suggests that RNASEL:p.Glu265* may be a genetic modifier of risk for early-onset breast cancer predisposition in carriers of high-risk mutations. Much larger case-case and case-control studies are warranted to test the association observed in this report.