Cancer Biomarkers

Lay summary

The large UKCTOCS biobank has provided exceptional opportunities to perform studies for novel cancer biomarker discovery and examine the association of novel or validation of new factors for cancer risk. The key strengths are: the large size, the cohort design, the detailed registry follow-up and the availability of epidemiological data obtained through questionnaires.

Team involved

Prof Usha Menon
Prof Ian Jacobs
Dr Aleksandra Gentry-Maharaj (co-ordinator for endometrial cancer)
Dr Evangelia-Ourania Fourkala (co-ordinator for breast cancer)
Dr Sophia Apostolidou (co-ordinator for Abcodia)
Dr Andy Ryan
Dr Matthew Burnell
Dr John Timms
Darren Thomas
Dr Ranjit Manchanda
Dr Ahmed Alatar
Dr Rema Iyer
Mr Rakshit Desai
Miss Chloe Karpinskyj

Breast cancer

Breast cancer is one of the major health problems facing the world today, being a significant contributor to overall morbidity and mortality. In order to make the greatest impact on breast cancer patients the following aspects need to be taken into account: 1) the identification of women predisposed to breast cancer by risk prediction markers and/or risk factors and 2) the application of a preventive or early detection strategy. This need is further magnified by the current controversies of the efficacy of breast cancer screening and the concern about over diagnosis and unnecessary treatment. In the last decades, a huge effort has been made to identify risk factors and biomarkers associated with breast cancer that can be used for risk stratification. Our group has a major interest in identifying novel biomarkers and factors that could be used for risk stratification and on that basis we have set up several internal studies and external collaborations.

Collaborators

Prof Joy Burchell and Prof Joyce Taylor-Papadimitriou (KCL) investigating MUC1 autoantibodies for the early detection of breast cancer.
Dr John Timms (UCL) investigating proteomic strategies for the identification of novel biomarkers for breast cancer risk prediction.
Prof Martin Widschwendter (UCL), Prof Hella Lichtenberg-Frate (University of Bonn) and Prof Anne Dawnay investigating the association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer.
Prof Martin Widschwendter (UCL) investigating serum DNA methylation changes in breast cancer.
Prof Martin Widschwendter (UCL) Prof Joseph Penninger (IMBA) investigating the association of RANKL/OPG/Progesterone in breast cancer.
Prof Tim Key (Oxford University) undertaking a meta-analysis on breast cancer and sex steroid hormones.
Prof Valerie Beral (Oxford University) analysing risk factors for breast cancer by including UKCTCOS data (Collaborative Group on Hormonal factors in Breast Cancer).
Prof Paul Taylor (CHIME UCL) and Prof Froud Ilyena (Barts’s, QMUL) investigating breast cancer risk and digital mammography.

Publications

Burford B*, Gentry-Maharaj A*, Graham R*, Allen D, Pedersen JW, Nudelman AS, Blixt |O, Fourkala E-O, Bueti D, Dawnay A, Ford J, Desai R, David L, Trinder P, Acres B, Schwientek T, Gammerman A, Reis CA, Silva L, Osório H, Hallett R, Wandall HH, Mandel U, Hollingsworth MA, Jacobs I, Fentiman I, Clausen H*, Taylor-Papadimitriou J*, Menon U3*, Burchell JM*. Autoantibodies to MUC1 cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer– nested case control study from UKCTOCS and Guernsey cohorts (British Journal of Cancer, in press)
Fourkala EO, Hauser-Kronberger C, Apostolidou S, Burnell M, Jones A, Grall J, Reitsamer R, Fiegl H, Jacobs I, Menon U, Widschwendter M. DNA methylation of polycomb group target genes in cores taken from breast cancer centre and periphery. Breast Cancer Res Treat. 2010 Apr;120(2):345-55.
Fourkala EO, Zaikin A, Burnell M, Gentry-Maharaj A, Ford J, Gunu R, Soromani C, Hasenbrink G, Jacobs I, Dawnay A, Widschwendter M, Lichtenberg-Fraté H, Menon U. Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women. Endocr Relat Cancer. 2012 Apr 10;19(2):137-47.
Fourkala EO, Gentry-Maharaj A, Burnell M, Ryan A, Manchanda R, Dawnay A, Jacobs I, Widschwendter M, Menon U. Histological confirmation of breast cancer registration and self-reporting in England and Wales: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening.
Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012 Nov;13(11):1141-51.

Conference presentations

Institute for Women’s’ Health Annual Meeting, London, UK, May 2012

Evangelia-Ourania Fourkala, Alexey Zaikin, Matthew Burnell, Aleksandra Gentry-Maharaj, Ian Jacobs, Anne Dawnay, Martin Widschwendter* and Usha Menon*. In postmenopausal women increased levels of testosterone and follicle stimulating hormone are associated with increased breast cancer risk: a nested case-control study within UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Institute for Women’s’ Health Annual Meeting, London, UK, May 2011

Evangelia O Fourkala, Mathhew Burnel, Aleksandra Gentry Maharaj, Hella Lichtenberg-Fraté, Guido Hasenbrink, Jeremy Ford, Ian Jacobs, Anne Dawney, H Brenner, Martin Widschwendter*, Usha Menon*. Serum Estrogen Receptor-a and ß Bioactivity are associated with Breast Cancer Risk.

Evangelia-Ourania Fourkala, Aleksandra Gentry-Maharaj, Matthew Burnell, Andy Ryan, Ranjit Manchanda, Anne Dawnay, Ian Jacobs, Martin Widschwendter, Usha Menon. Histological confirmation of breast cancer registration and self-reporting in England and Wales: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Innovations & Progress in Healthcare for Women, London, UK, Nov 2010

Institute for Women’s’ Health Annual Meeting, London, UK, Dec 2008

Evangelia-Ourania Fourkala, Cornelia Hauser-Kronberger, Sophia Apostolidou, Matthew Burnell, Allison Jones, Johannes Grall, Roland Reitsamer, Heidi Fiegl, Ian Jacobs, Usha Menon*, Martin Widschwendter*. Methylated PCGT gene loci in breast cancer are not affected by intratumour heterogeneity.

Colorectal cancer

Colorectal cancer is the third most common cancer in the UK and while 5 year survival rates are 75% if the disease is detected early, they decrease sharply to 5% in advanced stage disease. Early diagnosis and treatment of colorectal cancer are essential in reducing mortality by detecting the cancer at an early stage. In the UK, there is currently a national screening programme for bowel cancer (the NHS Bowel Screening programme) which uses Faecal Occult blood test (FOBt) as a primary screening test followed by colonoscopy in those that test positive. However, although FOBt has encouraging sensitivity, the compliance with the test is only 50%. Therefore, there is an urgent need to develop a blood bases marker that would either improve compliance or improve the performance of the test.

Collaborators

Dr Hans Wandall and Dr Johannes Pedersen (University of Copenhagen) to investigate the association of auto-antibodies with colon cancer.

Publications

Pedersen JW*, Gentry-Maharaj A*, Fourkala E-O, Dawnay A, Burnell M, Zaikin A, Pedersen AE, Jacobs I, Menon U**, Wandall H** Early detection of cancer in the general population - a blinded case control study of p53 auto-antibodies in colorectal cancer. Br J Cancer. 2013 Jan 15;108(1):107-14.

Endometrial cancer

Endometrial cancer is the most common gynaecological cancer in more developed countries and its incidence is increasing in postmenopausal women. Although majority of women present symptomatically and are diagnosed with early stage disease, when the disease is diagnosed at later stages, the survival rates are as low as for ovarian cancer. Major efforts have been made in the last few decades in fine tuning the screening strategies for the disease. Our group has a major interest in endometrial cancer and we have already reported on the performance characteristics of endometrial thickness as a screening tool which although demonstrated encouraging sensitivity does not currently have high enough sensitivity. Therefore the team is currently developing screening strategies using lifestyle/reproductive factors that may identify the women ‘at most risk’.

Collaborators

Dr Rosa Legood and Dr Alec Miners (London School of Hygiene and Tropical Medicine) investigating the lifetime effects, costs and cost-effectiveness of endometrial cancer screening.

Publications

Jacobs I, Gentry-Maharaj A, Burnell M, Manchanda R, Singh N, Sharma A, Ryan A, Seif M, Amso NN, Turner G, Brunell C, Fletcher G, Rangar R, Ford K, Godfrey K, Lopes A, Oram D, Herod J, Williamson K, Scott I, Jenkins H, Mould T, Woolas R, Murdoch J, Dobbs S, Leeson S, Cruickshank D, Skates SJ, Fallowfield L, Parmar M, Campbell S, Menon U. Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort. The lancet oncology, 2011. 12(1): p. 38-48.

Conference presentations

UCL EGA Institute for Women’s Health Annual meeting, 21 May 2012, London

Woolas R, Talaa A, Anderson M, Garner F, Brinkmann D, Ryan A, Gentry-Maharaj A, Kalsi J, Rosenthal A, Menon U, Jacobs I. A prospective study of endometrial thickness >10mm among 3646 women aged 50-80 years undergoing transvaginal ultrasound screening for ovarian cancer

International Gynaecological Cancer Society (IGCS) Meeting, 14 to 18 October 2006, Santa Monica

Oral presentation on Sensitivity and Specificity of Transvaginal Ultrasound Screening for Endometrial Cancer in 40,000 women from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) Jacobs I, Gentry-Maharaj A, Burnell M, Seif M, Amso N, Campbell S, Menon U for UKCTOCS

Ovarian cancer

Ovarian cancer is the fifth most common cancer in women. The prognosis of ovarian cancer is poor since women are commonly diagnosed with late stage disease i.e. stage III/IV, for which 5-year survival rates are around 27% and 16%. Better non-invasive tests for early detection of ovarian cancer are urgently required to reduce mortality due to this disease. Our group has a major interest in identifying novel biomarkers and factors that could be used for risk stratification/ screening and on that basis we have set up several internal studies and external collaborations.

Collaborators

Dr John Timms (UCL), Dr Rainer Cramer (Reading), Dr Alex Gammerman (RHUL) identifying novel biomarkers using proteomic technology for ovarian cancer risk prediction.
Prof Anna Lokshin (Pittsburgh) performing Luminex analysis for the identification/validation of novel biomarkers for ovarian cancer.
Prof Nicole Urban (Seattle) identifying/validating novel biomarkers for ovarian cancer.
Prof Robert Bast (Houston) developing a multi-marker algorithm in ovarian cancer.
Dr Alex Gammerman (RHUL) analysing symptoms for ovarian cancer.
Prof David Mark Robertson and Prof Andrew McCallum (Monash University) investigating the association of inhibin and ovarian cancer.

Pancreatic cancer

Pancreatic cancer is the fifth most common cause of cancer death, with a 5-year survival rate of only 3%. It often has a very poor prognosis since it is commonly not diagnosed until it is at an advanced stage and the cancer has metastasized. CA19.9 is the most widely used biomarker in the clinical diagnosis of pancreatic cancer. There are currently no screening methods for the early detection of pancreatic cancer. Several small studies exploring new biomarkers have shown encouraging results, but further work is needed to validate novel screening biomarkers for early detection of pancreatic cancer.

There has been major effort in exploring this further using the UKCTOCS biobank. The availability of samples in the years leading up to diagnosis, offers a unique opportunity for discovery and validation of novel, screening serum biomarkers. Currently a number of academic and industrial collaborations are underway aiming to identify potential biomarkers that in addition to CA19.9 may afford some utility for the early diagnosis of pancreatic cancer.

Collaborators

Dr John Timms (UCL) identifying novel biomarkers for pancreatic cancer.

Conference Presentations

UCL EGA Institute for Women’s Health Annual meeting, 21 May 2012, London
O’Brien DP, Sinclair J, Jenkinson C, Gentry-Maharaj A, Menon U, Costello E, Pereira SP, Timms JF. Quantitative Proteomic Strategies for the Discovery and Evaluation of Early Diagnostic Biomarkers for Pancreatic Cancer in Serum (GO).

British Society for Proteome Research, June 2011, Cambridge
O’Brien DP, Sinclair J, Jenkinson C, Gentry-Maharaj A, Menon U, Costello E, Pereira S, Timms JF Quantitative proteomic strategies for the discovery and evaluation of early diagnostic biomarkers for pancreatic cancer in serum.

Digestive week 2010, New Orleans
Sandanayake NS, Andreola F, Camuzeaux S, Sinclair J, Chapman MH, Webster G, Gentry-Maharaj A, Menon U, Jacobs I, Pereira SP, Timms,JF Serum CEACAM1 in the preclinical diagnosis of pancreatic adenocarcinoma.