Molecular Pathology of Lymphoma: Applications in Diagnosis and Prognosis
University of Cambridge
Tennis Court Road
Our research aims to characterise the genetics and molecular mechanism of several B and T-cell lymphoma entities and to improve their accurate diagnosis, prognosis and treatment stratifications. We are currently mainly working on the following areas:
1) MALT lymphoma: This is a group of low grade B-cell lymphomas arising from a background of chronic inflammatory disorders at various anatomic sites. Several genetic changes including t(11;18)/API2-MALT1, t(1;14)/BCL10-IGH, t(14;18)/IGH-MALT1, and TNFAIP3 (A20) inactivation mutation are seen, but at considerably variable frequencies in MALT lymphoma of different anatomic sites. Interestingly, all these genetic changes, albeit involving different genes, commonly dysregulate the NF-kB signalling pathway. We currently focus on profiling of the genetic changes in MALT lymphoma lacking the above genetic abnormalities, and investigate their potential oncogenic cooperation with antigenic drive from the underlying chronic inflammatory disorder.
2) Splenic marginal zone lymphoma (SMZL): By whole exome sequencing, we have recently identified KLF2 inactivating mutations as the most frequent genetic change (~40%) in SMZL. The KLF2 mutation is significantly associated with 7q32 deletion and IGVH1-2*04 rearrangement (encoding for an autoreactive BCR). In vitro functional studies indicate that KLF2 is a negative regulator of NF-kB. We currently investigate the molecular mechanism how KLF2 regulates NF-kB activity and its inactivation by mutation contributes to the development ofSMZL.
3) Diffuse large B-cell lymphoma (DLBCL): This is a highly heterogeneous group of aggressive B-cell lymphoma with variable responses to the current first line therapy. We are profiling the genetic changes of DLBCL in large series of population based cohort as well as patients from clinical trials with aim to identify those not responding to the current treatment and stratify them for targeted therapy based on their genetic profile/molecular mechanism.
4) Molecular diagnosis: We are active to develop methods and novel protocols that are emendable to routine formalin-fixed paraffin-embedded diagnostic tissue biopsies, thus to improve the application of research findings in routine clinical practice.
Ming Wang, Research Associate
Alex Clipson, Research Associate
Eguzkine Ochoa, Research Associate
Sarah Moody, Research Associate
Wenqing Yao, Visiting PhD Student
Collaborators: Hongxiang Liu
Liu H, Ye H, Ruskone-Fourmestraux A, De Jong D, Pileri S, Thiede C, Lavergne A, Boot H, Caletti G, Wundisch T, Molina T, Taal BG, Elena S, Thomas T, Zinzani PL, Neubauer A, Stolte M, Hamoudi RA, Dogan A, Isaacson PG, Du MQ. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication. Gastroenterology 2002;122:1286-94.
Isaacson PG, Du MQ. MALT lymphoma: from morphology to molecule. Nature Review Cancer 2004; 4:644-53.
Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A, Hamoudi RA, Noels H, Sagaert X, Van Loo P, Baens M, Du MQ, Lucas PC, McAllister-Lucas LM. Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 2011, 331:468-72.
Hamoudi RA, Appert A, Ye H, Ruskone-Fourmestraux A, Streubel B, Chott A, Raderer M, Gong L, Wlodarska I, De Wolf-Peeters C, MacLennan KA, de Leval L, Isaacson PG, Du MQ. Differential Expression of NF-kB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism. Leukaemia 2010;24:1487-97.
Bi Y, Zeng N, Chanudet E, Huang Y, Hamoudi RA, Liu H, Dong G, Watkins AJ, Ley SC, Zou L, Chen R, Zhu X, Du MQ. A20 inactivation in ocular adnexal MALT lymphoma. Haematologica 2012; 97:926-30.
Du MQ. MALT lymphoma: a paradigm of NF-kB deregulation. Seminars in Cancer Biology. 2016 doi: 10.1016/j.semcancer.
Splenic marginal zone lymphoma
Watkins AJ, Huang Y, Ye H, Chanudet E, Johnson N, Hamoudi RA, Liu H, Dong G, Attygalle A, McPhail ED, Law M, Isaacson PG, de Leval L, Wotherspoon A, Du MQ. Splenic Marginal Zone Lymphoma: characterization of 7q deletion and its value in diagnosis. Journal of Pathology 2010;220:461-74.
Yan Q, Huang Y, Watkins AJ, Kocialkowski S, Hamoudi RA, Isaacson PG, de Leval L, Wotherspoon A, Du MQ. BCR and TLR signalling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas. Haematologica 2012;97: 595-8.
Clipson A, Wang M, de Leval L, Ashton-Key M, Wotherspoon A, Vasilliou G, Bolli N, Grove C, Moody S, Escudero-Ibarz L, Gundem G, Brugger K, Xue X, Mi E, Bench A, Scott M, Liu H, Follows G, Robles EF, Martinez Climent JA, Oscier D, Watkins AJ, Du MQ. KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype. Leukemia 2015; 29: 1177-85.
Diffuse large B-cell lymphoma
Xue X, Zeng N, Gao Z, Du MQ. Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR. Laboratory Investigation. 2015; 95: 113-20.
Clipson A, Barrans S, Zeng N, Crouch S, Grigoropoulos NF, Liu H, Kocialkowski S, Wang M, Huang Y, Worrillow L, Goodlad J, Buxton J, Neat M, Fields P, Wilkins B, Grant JW, Wright P, EI-Daly H, Follows GA, Watkins AJ, Jack A, Du MQ. The prognosis of MYC translocation positive diffuse large B-cell lymphoma depends on the second hit. Journal of Pathology Clinical Research 30 Mar 2015 DOI: 10.1002/cjp2.10
Liu H, Bench AJ, Bacon CM,Payne K, Huang Y, Scott MA, Erber WN, Grant JW, Du MQ. A practical strategy for the routine use of BIOMED-2 PCR assays for detection of B- and T-cell clonality in diagnostic haematopathology. British Journal of Haematology 2007;138:31-43.
Liu H, Brais R, Lavergne-Slove A, Zeng Q, Payne K, Ye H, Liu Z, Carreras J, Huang Y, Bacon CM, Save V, Venkatraman L, Isaacson PG, Woodward J, Du MQ. Continual Monitoring of Intraepithelial Lymphocyte Immunophenotype and Clonality Is More Important Than Snapshot Analysis in the Surveillance of Refractory Coeliac Disease. Gut 2010; 59:452-60.
Wang M, Escudero-Ibarz L, Moody S, Zeng N, Clipson A, Huang Y, Xue X, Grigoropoulos NF, Barrans S, Worrillow L, Forshew t, Rosenfeld N, Su J, Firth A, Martin H, Jack A, Brugger K, Du MQ. Somatic mutation screening using archival formalin-fixed paraffin-embedded tissues by Fluidigm Access Array multiplex PCR and Illumina MiSeq sequencing. J Mol Diagn. 2015;17:521-32.