Sir Peter MacCallum Department of Oncology - Research Publications
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ItemSomatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants(OXFORD UNIV PRESS INC, 2022-10-31)BACKGROUND: Breast cancers (BCs) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1 and BRCA2, PALB2, and RAD51C, have been shown to exhibit biallelic loss in the respective genes and be associated with triple-negative breast cancer (TNBC) and distinctive somatic mutational signatures. Tumor sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development. METHODS: Exome sequencing was performed on paired normal-breast tumor DNA from 124 carriers of germline loss-of-function (LoF) or missense variant carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study. Biallelic inactivation and association with tumor genome features including mutational signatures and homologous recombination deficiency (HRD) score were investigated. RESULTS: BARD1-carrying TNBC (4 of 5) displayed biallelic loss and associated high HRD scores and mutational signature 3, as did a RAD51D-carrying TNBC and ovarian cancer. Biallelic loss was less frequent in BRIP1 BCs (4 of 13) and had low HRD scores. In contrast to other established BC genes, BCs from carriers of CHEK2 LoF (6 of 17) or missense (2 of 20) variant had low rates of biallelic loss. Exploratory analysis of BC from carriers of LoF variants in candidate genes such as BLM, FANCM, PARP2, and RAD50 found little evidence of biallelic inactivation. CONCLUSIONS: BARD1 and RAD51D behave as classic BRCA-like predisposition genes with biallelic inactivation, but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of biallelic inactivation does not provide definitive evidence against the gene's involvement in BC predisposition.
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ItemNo Preview Availablep53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study(WILEY, 2023-05)Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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ItemGene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes(AMER ASSOC CANCER RESEARCH, 2022-12-15)PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
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ItemCopy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci(OXFORD UNIV PRESS INC, 2022-10-10)BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
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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, 2022-07-01)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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ItemMolecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression(NATURE PORTFOLIO, 2022-06-29)Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score <2) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors (p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high (p = 0.02), PR-high (p = 0.03), stage III disease (p = 0.02), low residual disease burden (p = 0.01) and normal p16 expression (p<0.001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC.
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ItemPolygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)(SPRINGERNATURE, 2022-03-22)
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ItemPolygenic risk modeling for prediction of epithelial ovarian cancer risk(SPRINGERNATURE, 2022-01-14)Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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ItemCommon variants in breast cancer risk loci predispose to distinct tumor subtypes(BMC, 2022-01-04)BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.