Sir Peter MacCallum Department of Oncology - Research Publications

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    Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas
    Heinze, K ; Nazeran, TM ; Lee, S ; Kramer, P ; Cairns, ES ; Chiu, DS ; Leung, SCY ; Kang, EY ; Meagher, NS ; Kennedy, CJ ; Boros, J ; Kommoss, F ; Vollert, H-W ; Heitze, F ; du Bois, A ; Harter, P ; Grube, M ; Kraemer, B ; Staebler, A ; Kommoss, FKF ; Heublein, S ; Sinn, H-P ; Singh, N ; Laslavic, A ; Elishaev, E ; Olawaiye, A ; Moysich, K ; Modugno, F ; Sharma, R ; Brand, AH ; Harnett, PR ; DeFazio, A ; Fortner, RT ; Lubinski, J ; Lener, M ; Toloczko-Grabarek, A ; Cybulski, C ; Gronwald, H ; Gronwald, J ; Coulson, P ; El-Bahrawy, MA ; Jones, ME ; Schoemaker, MJ ; Swerdlow, AJ ; Gorringe, KL ; Campbell, I ; Cook, L ; Gayther, SA ; Carney, ME ; Shvetsov, YB ; Hernandez, BY ; Wilkens, LR ; Goodman, MT ; Mateoiu, C ; Linder, A ; Sundfeldt, K ; Kelemen, LE ; Gentry-Maharaj, A ; Widschwendter, M ; Menon, U ; Bolton, KL ; Alsop, J ; Shah, M ; Jimenez-Linan, M ; Pharoah, PDP ; Brenton, JD ; Cushing-Haugen, KL ; Harris, HR ; Doherty, JA ; Gilks, B ; Ghatage, P ; Huntsman, DG ; Nelson, GS ; Tinker, A ; Lee, C-H ; Goode, EL ; Nelson, BH ; Ramus, SJ ; Kommoss, S ; Talhouk, A ; Kobel, M ; Anglesio, MS (Wiley, 2022-04)
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    Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
    Meagher, NS ; Gorringe, KL ; Wakefield, M ; Bolithon, A ; Pang, CNI ; Chiu, DS ; Anglesio, MS ; Mallitt, K-A ; Doherty, JA ; Harris, HR ; Schildkraut, JM ; Berchuck, A ; Cushing-Haugen, KL ; Chezar, K ; Chou, A ; Tan, A ; Alsop, J ; Barlow, E ; Beckmann, MW ; Boros, J ; Bowtell, DDL ; Brand, AH ; Brenton, JD ; Campbell, I ; Cheasley, D ; Cohen, J ; Cybulski, C ; Elishaev, E ; Erber, R ; Farrell, R ; Fischer, A ; Fu, Z ; Gilks, B ; Gill, AJ ; Gourley, C ; Grube, M ; Harnett, PR ; Hartmann, A ; Hettiaratchi, A ; Hogdall, CK ; Huzarski, T ; Jakubowska, A ; Jimenez-Linan, M ; Kennedy, CJ ; Kim, B-G ; Kim, J-W ; Kim, J-H ; Klett, K ; Koziak, JM ; Lai, T ; Laslavic, A ; Lester, J ; Leung, Y ; Li, N ; Liauw, W ; Lim, BWX ; Linder, A ; Lubinski, J ; Mahale, S ; Mateoiu, C ; McInerny, S ; Menkiszak, J ; Minoo, P ; Mittelstadt, S ; Morris, D ; Orsulic, S ; Park, S-Y ; Pearce, CL ; Pearson, J ; Pike, MC ; Quinn, CM ; Mohan, GR ; Rao, J ; Riggan, MJ ; Ruebner, M ; Salfinger, S ; Scott, CL ; Shah, M ; Steed, H ; Stewart, CJR ; Subramanian, D ; Sung, S ; Tang, K ; Timpson, P ; Ward, RL ; Wiedenhoefer, R ; Thorne, H ; Cohen, PA ; Crowe, P ; Fasching, PA ; Gronwald, J ; Hawkins, NJ ; Hogdall, E ; Huntsman, DG ; James, PA ; Karlan, BY ; Kelemen, LE ; Kommoss, S ; Konecny, GE ; Modugno, F ; Park, SK ; Staebler, A ; Sundfeldt, K ; Wu, AH ; Talhouk, A ; Pharoah, PDP ; Anderson, L ; DeFazio, A ; Kobel, M ; Friedlander, ML ; Ramus, SJ (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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    Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression
    Cheasley, D ; Fernandez, ML ; Kobel, M ; Kim, H ; Dawson, A ; Hoenisch, J ; Bittner, M ; Chiu, DS ; Talhouk, A ; Gilks, CB ; Jayawardana, MW ; Pishas, K ; Mes-Masson, A-M ; Provencher, D ; Nigam, A ; Hacker, NF ; Gorringe, KL ; Campbell, IG ; Carey, MS (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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    Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
    Li, N ; Lim, BWX ; Thompson, ER ; McInerny, S ; Zethoven, M ; Cheasley, D ; Rowley, SM ; Wong-Brown, MW ; Devereux, L ; Gorringe, KL ; Sloan, EK ; Trainer, A ; Scott, RJ ; James, PA ; Campbell, IG (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, pā€‰=ā€‰9.05ā€‰Ć—ā€‰10-9) and missense (OR 1.27, pā€‰=ā€‰3.96ā€‰Ć—ā€‰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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    Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
    Li, N ; Zethoven, M ; McInerny, S ; Devereux, L ; Huang, Y-K ; Thio, N ; Cheasley, D ; Gutierrez-Enriquez, S ; Moles-Fernandez, A ; Diez, O ; Nguyen-Dumont, T ; Southey, MC ; Hopper, JL ; Simard, J ; Dumont, M ; Soucy, P ; Meindl, A ; Schmutzler, R ; Schmidt, MK ; Adank, MA ; Andrulis, IL ; Hahnen, E ; Engel, C ; Lesueur, F ; Girard, E ; Neuhausen, SL ; Ziv, E ; Allen, J ; Easton, DF ; Scott, RJ ; Gorringe, KL ; James, PA ; Campbell, IG (NATURE RESEARCH, 2021-05-12)
    Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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    Primary mucinous ovarian neoplasms rarely show germ cell histogenesis
    Kommoss, FKF ; Cheasley, D ; Wakefield, MJ ; Scott, CL ; Campbell, IG ; Gilks, CB ; Gorringe, K (WILEY, 2021-03)
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    Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities
    Cheasley, D ; Nigam, A ; Zethoven, M ; Hunter, S ; Etemadmoghadam, D ; Semple, T ; Allan, P ; Carey, MS ; Fernandez, ML ; Dawson, A ; Kobel, M ; Huntsman, DG ; Le Page, C ; Mes-Masson, A-M ; Provencher, D ; Hacker, N ; Gao, Y ; Bowtell, D ; deFazio, A ; Gorringe, KL ; Campbell, IG (WILEY, 2021-01)
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    Therapeutic options for mucinous ovarian carcinoma
    Gorringe, KL ; Cheasley, D ; Wakefield, MJ ; Ryland, GL ; Allan, PE ; Alsop, K ; Amarasinghe, KC ; Ananda, S ; Bowtell, DDL ; Christie, M ; Chiew, Y-E ; Churchman, M ; DeFazio, A ; Fereday, S ; Gilks, CB ; Gourley, C ; Hadley, AM ; Hendley, J ; Hunter, SM ; Kaufmann, SH ; Kennedy, CJ ; Kobel, M ; Le Page, C ; Li, J ; Lupat, R ; McNally, OM ; McAlpine, JN ; Pyman, J ; Rowley, SM ; Salazar, C ; Saunders, H ; Semple, T ; Stephens, AN ; Thio, N ; Torres, MC ; Traficante, N ; Zethoven, M ; Antill, YC ; Campbell, IG ; Scott, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-03)
    OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
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    Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei
    Lung, MS ; Mitchell, CA ; Doyle, MA ; Lynch, AC ; Gorringe, KL ; Bowtell, DDL ; Campbell, IG ; Trainer, AH (BMC, 2020-05-01)
    BACKGROUND: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. METHODS: Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ā‰„10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. RESULTS: Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified. CONCLUSION: Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
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    Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes
    Subramanian, DN ; Zethoven, M ; McInerny, S ; Morgan, JA ; Rowley, SM ; Lee, JEA ; Li, N ; Gorringe, KL ; James, PA ; Campbell, IG (NATURE PORTFOLIO, 2020-04-02)
    High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (pā€‰<ā€‰0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.