Molecular Pathology
Staff
Funding
Collaborators
Recent Publications
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Lab Head: Professor Sunil Lakhani
Sunil.Lakhani@qimr.edu.au
Breast cancer is a heterogeneous disease encompassing numerous pathological entities and diverse clinical behaviour. Our two major,
interrelated areas of work attempt to unravel this heterogeneity by using molecular pathology to sub-classify breast cancer into more
biologically meaningful diagnostic categories and to further our understanding of the multi-step model of breast carcinogenesis.
Lobular Carcinoma
Invasive lobular carcinoma (ILC) is the second most commonly diagnosed histological type, comprising approximately 10-15% of all breast cancers.
We have studied the molecular genetic profiles of ILC using microarray comparative genomic hybridisation (aCGH) and have identified genomic
amplifications of 8p12-p11.2 (FGFR1) and 11q13 (CCND1) which are likely to be important in tumour development. We have also shown that the
high grade, poor prognosis variant pleomorphic lobular carcinoma (PLC) has a similar aCGH profile to ILC with additional amplification of
oncogenes such as ERBB2 (17q12) and c-MYC (8q24).
The majority of ILC also exhibit loss or reduced E-cadherin expression and this is likely to be associated with the characteristic discohesive growth pattern of these tumours. Some diagnostic pathologists are now using E-cadherin positive staining to discount a diagnosis of ILC in favour of invasive ductal carcinoma (IDC). ILC and IDC have notable differences in their biology and clinical nature and so this has implications in the management strategy for a patient. We have demonstrated that ILCs with mutations in E-Cadherin can occasionally express the protein and we are currently studying cases of ILC morphology and mixed E-cadherin immunoreactivity to understand the role of E-cadherin in the biology of lobular lesions and evaluate the limitations of its use in clinical practice. Our lab is also extending these studies into lobular carcinoma arising within families with a hereditary predisposition..
There is strong evidence that lobular carcinoma in situ (LCIS) and ILC are associated with an inherited predisposition. They are both frequently multifocal and bilateral, a feature seen in many familial disorders, and a higher rates of ILC is found in familial BRCAx mutation carriers compared to sporadic controls. We are using the kConFab resource to study this association in high risk families. PLC may be part of the BRCA2 spectrum of tumours and we see molecular evidence to support this with loss of the BRCA2 genomic region by aCGH. We plan to study kConFab breast tumours to investigate the role of BRCA2 in this ILC variant.
Basal-like' breast cancer
A subgroup of high grade IDC (~25%) that has received great attention in the last few years is one which shows a 'basal' phenotype, i.e.
tumours which express markers of basal/myoepithelial cells such as cytokeratins 5/6 and 14 in addition to the luminal markers expressed
by all IDCs. These tumours are usually high grade (grade III), and are oestrogen receptor (ER), progesterone receptor (PR), and HER-2
negative (triple negative). We have shown that some patients have a relatively 'good' prognosis while others have a very poor outcome.
This poor outcome may be associated with the more frequent occurrence of brain metastases, since such patients rarely live longer than
2 years following diagnosis. We are analysing a series of primary breast tumours and their matched brain metastases for the expression
of a range of markers associated with metastasis and carrying out expression microarrays and CGH to establish molecular alterations
that are associated with tumours that give rise to brain metastases compared to those that do not. We hope to be able to identify
mechanisms that give advantage to the cells in establishing a tumour deposit in the brain and hence develop therapeutic strategies
to combat this.
Genetics of Normal Breast and Stem Cells
We have previously demonstrated that normal breast epithelial cells harbour genetic alterations seen in malignancy, albeit at a very low frequency. These alterations were identified in both the luminal cell and myoepithelial cell compartment, suggesting that alterations probably occurred in progenitors prior to lineage differentiation. There has also been speculation that 'basal' breast tumours may originate from stem cells since they express phenotypic markers of more than one cell type. In collaboration with the Queensland Brain Institute, we are investigating whether these tumours are likely to be derived from stem cells, or if phenotypic plasticity of another cell type may be involved. Molecular profiling of different normal and tumour cell populations from the breast, including the putative stem cells, will allow us to investigate which pathways may be involved in the development of 'basal' breast cancers.
Staff
| Labhead: | Professor Sunil Lakhani | |
| Postdoctoral Fellows: | Dr Peter Simpson Dr Chanel Smart | |
| Research Assistants: | Patricia Keith Lynne Reid Janani Jayantan |
|
| Clinical Fellows: | Dr Leonard da Silva Dr Pria Pakkiri |
|
| Visiting Fellow: | Ana Cristina Vargas (MExico) | |
| Tissue Bank Manager: | Soori Manu |
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Funding
National Health and Medical Research Council
The University of Queensland
Ludwig Institute for Cancer Research
Pathology Queensland
VMO Liaison Committee and Queensland Health
AMAQ Foundation
The Wesley Research Institute
Collaborators
- Dr Georgia Chenevix-Trench (QIMR)
- Dr Kum Kum Khanna (QIMR)
- Assoc Prof Alejandro Lopez (QIMR)
- Dr Mandy Spurdle (QIMR)
- Dr Melissa Brown & Dr Chanel Smart (University of Queensland)
- Dr Greg Monteith (University of Queensland)
- Prof Brent Reynolds (University of Queensland)
- Prof Mike Stratton (Sanger Research Centre, UK)
- Prof Colin Furnival (Royal Brisbane and Women's Hospital)
- kConFab
- Dr Glen Francis (PA Hospitlal)
- Dr Geoff Beadle (QIMR, RBWH & Wesley Hospital)
- Dr Alan Porter (Wesley Hospital)
- Dr David Papadimos (Sullivan Nicolades Pathology)
- Drs Rosemary Ballien & Michale Bilous (Sydney)
- Prof Stephen Fox (Melbourne)
- Dr Frederique Penault-Llorca (Clermont Ferrand, France)
- Dr Jorge Reis Filho (Breakthrough Breast Cancer, UK)
- Drs Michal Michal & Alena Skalova (Czech Republic)
Selected Publications
Lakhani S., Easton D., Stratton M.R. (1997). Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 349: 1505-1510.
Lakhani S.R., Jacquemier J., Sloane J.P., Gusterson B.A., Anderson T.J., van de Vijver M.J., Farid L.M., Venter D., Antoniou A., Storfer-Isser A., Smyth E., Steel C.M., Haites N., Scott R.J., Goldgar D., Neuhausen S., Daly P.A., Ormiston W., McManus R., Scherneck S., Ponder B.A., Ford D., Peto J., Stoppa-Lyonnet D., Easton D.F., et al. (1998). Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90: 1138-1145.
Lakhani S.R., Gusterson B.A., Jacquemier J., Sloane J.P., Anderson T.J., van de Vijver M.J., Venter D., Freeman A., Antoniou A., McGuffog L., Smyth E., Steel C.M., Haites N., Scott R.J., Goldgar D., Neuhausen S., Daly P.A., Ormiston W., McManus R., Scherneck S., Ponder B.A., Futreal P.A., Peto J., Stoppa-Lyonnet D., Bignon Y.J., Stratton M.R. (2000). The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 6: 782-789.
Lakhani S.R., Ashworth A. (2001). Microarray and histopathological analysis of tumours: the future and the past? Nat Rev Cancer 1: 151-157.
Lakhani S.R., O'Hare M.J., Ashworth A. (2001). Profiling familial breast cancer. Nat Med 7: 408-410.
Lakhani S.R., Van De Vijver M.J., Jacquemier J., Anderson T.J., Osin P.P., McGuffog L., Easton D.F. (2002). The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20: 2310-2318.
Simpson P.T., Gale T., Fulford L.G., Reis-Filho J.S., Lakhani S.R. (2003). The diagnosis and management of pre-invasive breast disease: pathology of atypical lobular hyperplasia and lobular carcinoma in situ. Breast Cancer Res 5: 258-262.
Jones C., Mackay A., Grigoriadis A., Cossu A., Reis-Filho J.S., Fulford L., Dexter T., Davies S., Bulmer K., Ford E., Parry S., Budroni M., Palmieri G., Neville A.M., O'Hare M.J., Lakhani S.R. (2004). Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer. Cancer Res 64: 3037-3045.
Simpson P.T., Gale T., Reis-Filho J.S., Jones C., Parry S., Steele D., Cossu A., Budroni M., Palmieri G., Lakhani S.R. (2004). Distribution and significance of 14-3-3sigma, a novel myoepithelial marker, in normal, benign, and malignant breast tissue. J Pathol 202: 274-285.
Clarke C.L., Sandle J., Parry S.C., Reis-Filho J.S., O'Hare M.J., Lakhani S.R. (2004). Cytokeratin 5/6 in normal human breast: lack of evidence for a stem cell phenotype. J Pathol 204: 147-152.
Jones C., Ford E., Gillett C., Ryder K., Merrett S., Reis-Filho J.S., Fulford L.G., Hanby A., Lakhani S.R. (2004). Molecular cytogenetic identification of subgroups of grade III invasive ductal breast carcinomas with different clinical outcomes. Clin Cancer Res 10: 5988-5997.
Stephens P., Edkins S., Davies H., Greenman C., Cox C., Hunter C., Bignell G., Teague J., Smith R., Stevens C., O'Meara S., Parker A., Tarpey P., Avis T., Barthorpe A., Brackenbury L., Buck G., Butler A., Clements J., Cole J., Dicks E., Edwards K., Forbes S., Gorton M., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jones D., Kosmidou V., Laman R., Lugg R., Menzies A., Perry J., Petty R., Raine K., Shepherd R., Small A., Solomon H., Stephens Y., Tofts C., Varian J., Webb A., West S., Widaa S., Yates A., Brasseur F., Cooper C.S., Flanagan A.M., Green A., Knowles M., Leung S.Y., Looijenga L.H., Malkowicz B., Pierotti M.A., Teh B., Yuen S.T., Nicholson A.G., Lakhani S., Easton D.F., Weber B.L., Stratton M.R., Futreal P.A., Wooster R. (2005). A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet 37: 590-592.
Reis-Filho J.S., Simpson P.T., Jones C., Steele D., Mackay A., Iravani M., Fenwick K., Valgeirsson H., Lambros M., Ashworth A., Palacios J., Schmitt F., Lakhani S.R. (2005). Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol 207: 1-13.
Simpson P.T., Gale T., Reis-Filho J.S., Jones C., Parry S., Sloane J.P., Hanby A., Pinder S.E., Lee A.H., Humphreys S., Ellis I.O., Lakhani S.R. (2005). Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis. Am J Surg Pathol 29: 734-746.
Lakhani S.R., Reis-Filho J.S., Fulford L., Penault-Llorca F., van der Vijver M., Parry S., Bishop T., Benitez J., Rivas C., Bignon Y.J., Chang-Claude J., Hamann U., Cornelisse C.J., Devilee P., Beckmann M.W., Nestle-Kramling C., Daly P.A., Haites N., Varley J., Lalloo F., Evans G., Maugard C., Meijers-Heijboer H., Klijn J.G., Olah E., Gusterson B.A., Pilotti S., Radice P., Scherneck S., Sobol H., Jacquemier J., Wagner T., Peto J., Stratton M.R., McGuffog L., Easton D.F. (2005). Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11: 5175-5180.
Simpson P.T., Reis-Filho J.S., Gale T., Lakhani S.R. (2005). Molecular evolution of breast cancer. J Pathol 205: 248-254.
Clarke C, Sandle J, Lakhani S.R. Myoepithelial cells: pathology, cell separation and markers of myoepithelial differentiation. J Mammary Gland Biol 2005; 10: 273-80.
Chenevix-Trench G., Healey S., Lakhani S., Waring P., Cummings M., Brinkworth R., Deffenbaugh A.M., Burbidge L.A., Pruss D., Judkins T., Scholl T., Bekessy A., Marsh A., Lovelock P., Wong M., Tesoriero A., Renard H., Southey M., Hopper J.L., Yannoukakos K., Brown M., Easton D., Tavtigian S.V., Goldgar D., Spurdle A.B. (2006). Genetic and Histopathologic Evaluation of BRCA1 and BRCA2 DNA Sequence Variants of Unknown Clinical Significance. Cancer Res 66: 2019-2027.
Clarke CL, Sandle J, Jones AA, Sofronis A, Patani NR, Lakhani SR. Mapping loss of heterozygosity in normal human breast cells from BRCA1/2 carriers. Br J Cancer 2006; 95: 515-9.
Reis-Filho JS, Simpson PT, Turner NC, Lambros MB, Jones C, Mackay A, Grigoriadis A, Sarrio D, Savage K, Dexter T, Iravani M, Fenwick K, Weber B, Hardisson D, Schmitt FC, Palacios J, Lakhani SR, Ashworth A. FGFR1 Emerges as a Potential Therapeutic Target for Lobular Breast Carcinomas. Clin Cancer Res 2006; 12: 6652-62.
Marsh A., Healey S., Lewis A., Spurdle A.B., Kedda M.A., Khanna K.K., Mann G.J., Pupo G.M., Lakhani S.R., Chenevix-Trench G. (2006). Mutation analysis of five candidate genes in familial breast cancer. Breast Cancer Res Treat 105:377-389.
Fulford L.G., Reis-Filho J.S., Ryder K., Jones C., Gillett C.E., Hanby A., Easton D., Lakhani S.R. (2007). Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res 9: R4
Da Silva, L., Clarke C., Lakhani S.R. (2007). Demystifying basal-like breast carcinomas. J Clin Pathol 60:1328-1332.
Eccles D., Gerty S., Simmonds P., Hammond V., Ennis S., Altman D.G. and the POSH steering group (Lakhani S.R. et al) (2007). Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol. BMC Cancer 7:160
Simpson P.T., Da Silva L.M., Lakhani S.R. (2007). In Situ Carcinoma-Can We Predict which Patient Will Come Back with a Recurrence? Cancer Cell 12:409-411.
Da Silva L., Parry S., Reid L., Keith P., Waddell N., Kossai M., Clarke C., Lakhani S.R., Simpson P.T. (2008). Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. May;32(5):773-83
Lovelock P.K., Spurdle A.B., Mok M.T., Farrugia D.J., Lakhani S.R., Healey S., Arnold S., Buchanan D., Investigators K., Couch F.J., Henderson B.R., Goldgar D.E., Tavtigian S.V., Chenevix-Trench G., Brown M.A. (2007). Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res 9:6:R82
Smart C.E., Clarke C., Brooks K.M., Raghavendra A., Brewster B.L., French J.D., Hetherington R., Fleming J.S., Rothnagel J.A., Wainwright B., Lakhani S.R., Brown M.A. (2007). Targeted disruption of Brca1 in restricted compartments of the mouse mammary epithelia. Breast Cancer Res Treat
Spurdle A.B., Lakhani S.R., Healey S., Parry S., Da Silva L.M., Brinkworth R., Hopper J.L., Brown M.A., Babikyan D., Chenevix-Trench G., Tavtigian S.V., Goldgar D.E. (2008). Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants: The Value of Cytokeratin Profiles and Evolutionary Analysis--A Report From the kConFab Investigators. J Clin Oncol 26:10:1657-1663.
Wayte N., Da Silva L., Chenevix-Trench G., Lakhani S.R. (2008). What's in a cancer syndrome? Genes, phenotype and pathology. Pathology 40:3:247-259