The Gorringe lab focuses on cancer precision medicine: applying genomics to clinical questions in breast and ovarian cancers.
Personalized Risk Evaluation in breast Ductal Carcinoma in situ (PRECISION)
Ductal carcinoma in situ (DCIS) accounts for 20-25% of breast cancer and is a growing health problem, with great variation in treatment and outcome. After local excision, about 25% of DCIS will recur. There are no robust markers of recurrence risk for tailoring treatment to optimise patient outcome and minimise treatment toxicity. Thus, clinical management of DCIS is challenging and many women are over-treated while others might benefit from more intense therapy or monitoring. We aim to develop a clinical test for personalised DCIS recurrence risk, using gene copy number, immunohistochemistry and gene expression assays. This study will leverage unique local and international DCIS cohorts that have extensive clinical annotation and follow-up data. A similar study for benign breast lesions (atypical ductal hyperplasia and papillomas) is also being undertaken.
Genomic characterisation of rare ovarian epithelial carcinoma subtypes
While the genomic profiles of high-grade serous carcinomas have been extensively studied, little is known about the low-grade serous and mucinous subtypes. A major current initiative is the comprehensive Genomic Analysis of Mucinous Tumours (GAMuT) study, which analyses primary ovarian and extra-ovarian metastases with mucinous histology using copy number, expression and exome sequencing. The goals are to identify novel targets for therapy and to determine whether mucinous tumours from multiple tissue origins share genomic characteristics. A similar project is underway in low-grade serous carcinomas.
In addition, we are generating novel in vitro (organoid) and in vivo models for these rare diseases in order to test novel therapies and functionally characterise putative cancer genes.
Investigation of GAB2 as a biomarker for therapy response in ovarian cancer
Targeted therapies offer new hope for ovarian cancer, and the PI3K/mTOR/AKT pathway is an area of intense drug development. We identified GAB2 as a candidate biomarker of response to PI3K/mTOR/AKT inhibition in ovarian cancer. This protein, a key component of the pathway that mediates signals from receptor tyrosine kinases to downstream components, shows high expression in cell lines that are sensitive to inhibition. We will evaluate whether GAB2 determines cellular sensitivity to PI3K/mTOR/AKT inhibition.
Meagher NS, et al... Gorringe KL, Pharoah PDP, Minoo P, Stewart C, Bathe OF, Gui X, Cohen P, Ramus SJ, Köbel M. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases. Mod Pathol. 2019 Jun 25. doi: 10.1038/s41379-019-0302-0
Toss MS, Miligy IM, Gorringe KL, Aleskandarany MA, Alkawaz A, Mittal K, Aneja R, Ellis IO, Green AR, Rakha EA. Collagen (XI) alpha-1 chain is an independent prognostic factor in breast ductal carcinoma in situ. Mod Pathol. 2019 Jun 7. doi: 10.1038/s41379-019-0286-9
Kader T, Hill P, Zethoven M, Goode DL, Elder K, Thio N, Doyle M, Semple T, Sufyan W, Byrne DJ, Pang JB, Murugasu A, Miligy IM, Green AR, Rakha EA, Fox SB, Mann GB, Campbell IG, Gorringe KL. Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma. J Pathol. 2019 Jul;248(3):326-338. doi: 10.1002/path.5262
Li N, McInerny S, Zethoven M, Cheasley D, Lim BWX, Rowley SM, Devereux L, Grewal N, Ahmadloo S, Byrne D, Lee JEA, Li J, Fox SB, John T, Antill Y, Gorringe KL, James PA, Campbell IG. Combined tumor sequencing and case/control analyses of RAD51C in breast cancer. J Natl Cancer Inst. 2019 Apr 5. pii: djz045. doi: 10.1093/jnci/djz045
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 JM, 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. Molecular comparison of interval and screen-detected breast cancers. J Pathol. 2019 Jun;248(2):243-252. doi: 10.1002/path.5251
Salazar C, Campbell IG, Gorringe KL. When Is "Type I" Ovarian Cancer Not "Type I"? Indications of an Out-Dated Dichotomy. Front Oncol. 2018 Dec 21;8:654. doi: 10.3389/fonc.2018.00654
Li N, Rowley SM, Goode DL, Amarasinghe KC, McInerny S, Devereux L; LifePool Investigators, Wong-Brown MW, Lupat R, Lee JEA, Hughes S, Thompson ER, Zethoven M, Li J, Trainer AH, Gorringe KL, Scott RJ, James PA, Campbell IG. Mutations in RECQL are not associated with breast cancer risk in an Australian population. Nat Genet. 2018 Oct;50(10):1346-1348. doi: 10.1038/s41588-018-0206-9
Kader T, Hill P, Rakha EA, Campbell IG, Gorringe KL. Atypical ductal hyperplasia: update on diagnosis, management, and molecular landscape. Breast Cancer Res. 2018 May 2;20(1):39. doi: 10.1186/s13058-018-0967-1
Gorringe KL, Fox SB. Ductal Carcinoma In Situ Biology, Biomarkers, and Diagnosis. Front Oncol. 2017 Oct 23;7:248. doi: 10.3389/fonc.2017.00248
Hendry S, Pang JB, Byrne DJ, Lakhani SR, Cummings MC, Campbell IG, Mann GB, Gorringe KL*, Fox SB*. Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features. Clin Cancer Res. 2017 Sep 1;23(17):5210-5217. doi: 10.1158/1078-0432.CCR-17-0743
Pang JB, Savas P, Fellowes AP, Mir Arnau G, Kader T, Vedururu R, Hewitt C, Takano EA, Byrne DJ, Choong DY, Millar EK, Lee CS, O'Toole SA, Lakhani SR, Cummings MC, Mann GB, Campbell IG, Dobrovic A, Loi S, Gorringe KL*, Fox SB*. Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer. Mod Pathol. 2017 Jul;30(7):952-963. doi: 10.1038/modpathol.2017.21
Kader T, Goode DL, Wong SQ, Connaughton J, Rowley SM, Devereux L, Byrne D, Fox SB, Mir Arnau G, Tothill RW, Campbell IG, Gorringe KL. Copy number analysis by low coverage whole genome sequencing using ultra low-input DNA from formalin-fixed paraffin embedded tumor tissue. Genome Med. 2016 Nov 15;8(1):121
Pang JM, Gorringe KL, Fox SB. Ductal carcinoma in situ - update on risk assessment and management. Histopathology. 2016 Jan;68(1):96-109. doi: 10.1111/his.12796
Chrysanthou E*, Gorringe KL*, Joseph C, Craze M, Nolan CC, Diez-Rodriguez M, Green AR, Rakha EA, Ellis IO, Mukherjee A. Phenotypic characterisation of breast cancer: the role of CDC42. Breast Cancer Res Treat. 2017 Jul;164(2):317-325. doi: 10.1007/s10549-017-4267-8
Gorringe KL, Hunter SM, Pang JM, Opeskin K, Hill P, Rowley SM, Choong DY, Thompson ER, Dobrovic A, Fox SB, Mann GB, Campbell IG (2015). Copy number analysis of ductal carcinoma in situ with and without recurrence. Mod Pathol.28(9):1174-84.
Hunter SM, Anglesio MS, Ryland GL, Sharma R, Chiew YE, Rowley SM, Doyle MA, Li J, Gilks CB, Moss P, Allan PE, Stephens AN, Huntsman DG, deFazio A, Bowtell DD, Australian Ovarian Cancer Study Group, Gorringe KL, Campbell IG (2015). Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget.6(35):37663-77.
Davis, SJ, Sheppard KE, Anglesio MA, George J, Traficante N, Fereday S, Intermaggio MP, Menon U, Gentry-Maharaj A, Lubinksi J, Gronwald J, Pearce CL, Pike MC, Wu A, Kommoss S, Pfisterer J, du Bois A, Hilpert F, Ramus SJ, Bowtell DDL, Huntsman DG, Pearson RB, Simpson KJ, Campbell IG, Gorringe KL (2015). Enhanced GAB2 expression is associated with improved survival in high-grade serous ovarian cancer and sensitivity to PI3K inhibition. Mol Cancer Ther.14(6):1495-503.
Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, Christie M, Allan PE, Stephens AN, Bowtell DD, Australian Ovarian Cancer Study Group, Campbell IG, Gorringe KL (2015). Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. Genome Med.7(1):87.
Ryland GL, Hunter SM, Doyle MA, Rowley SM, Christie M, Allan PE, Bowtell DD, Australian Ovarian Cancer Study Group, Gorringe KL, Campbell IG (2013). RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. J Pathol.229(3):469-76.
Li J, Lupat R, Amarasinghe KC, Thompson ER, Doyle MA, Ryland GL, Tothill RW, Halgamuge SK, Campbell IG, Gorringe KL (2012). CONTRA: copy number analysis for targeted resequencing. Bioinformatics.28(10):1307-13.