Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 34
  • Item
    Thumbnail Image
    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, 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.
  • Item
    Thumbnail Image
    Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma
    Kader, T ; Hill, P ; Zethoven, M ; Goode, DL ; Elder, K ; Thio, N ; Doyle, M ; Semple, T ; Sufyan, W ; Byrne, DJ ; Pang, J-MB ; Murugasu, A ; Miligy, IM ; Green, AR ; Rakha, EA ; Fox, SB ; Mann, GB ; Campbell, IG ; Gorringe, KL (WILEY, 2019-07-01)
  • Item
    Thumbnail Image
    Molecular comparison of interval and screen-detected breast cancers
    Cheasley, D ; Li, N ; Rowley, SM ; Elder, K ; Mann, GB ; Loi, S ; Savas, P ; Goode, DL ; Kader, T ; Zethoven, M ; Semple, T ; Fox, SB ; Pang, J-M ; Byrne, D ; Devereux, L ; Nickson, C ; Procopio, P ; Lee, G ; Hughes, S ; Saunders, H ; Fujihara, KM ; Kuykhoven, K ; Connaughton, J ; James, PA ; Gorringe, KL ; Campbell, IG (WILEY, 2019-06-01)
  • Item
    Thumbnail Image
    Molecular analysis of PALB2-associated breast cancers
    Lee, JEA ; Li, N ; Rowley, SM ; Cheasley, D ; Zethoven, M ; McInerny, S ; Gorringe, KL ; James, PA ; Campbell, IG (WILEY, 2018-05-01)
  • Item
    Thumbnail Image
    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.
  • Item
    Thumbnail Image
    Primary mucinous ovarian neoplasms rarely show germ cell histogenesis
    Kommoss, FKF ; Cheasley, D ; Wakefield, MJ ; Scott, CL ; Campbell, IG ; Gilks, CB ; Gorringe, K (WILEY, 2020-12-29)
  • Item
    Thumbnail Image
    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, 2020-10-28)
  • Item
    Thumbnail Image
    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, 2020-03-01)
    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.
  • Item
    No Preview Available
    A rational approach to cancer therapy.
    Gorringe, KL ; Campbell, IG (Springer Science and Business Media LLC, 2008)
  • Item
    Thumbnail Image
    Analysis of the Mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer
    Davis, SJ ; Choong, DYH ; Ramakrishna, M ; Ryland, GL ; Campbell, IG ; Gorringe, KL (BMC, 2011-05-17)
    BACKGROUND: MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer. METHODS: We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines. RESULTS: In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation. CONCLUSIONS: MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.