MALT lymphomas--a closer look in the Genomics era.

In 1832, an article titled "On some morbid appearances of the absorbent glands and spleen" was published in the journal 'Medico-Chirurgical Transactions'. (1) The author was Thomas Hodgkin (Fig. 1). Thus began an era of the study of a distinct group of tumors involving the lymphatic system, what we refer to today as the 'lymphomas.' Presently, lymphoid neoplasms are usually classified into Hodgkin and non-Hodgkin lymphomas. The current WHO classification describes more than 30 different types of non-Hodgkin lymphomas. (2) Among these, the three most common types include the diffuse large B-cell lymphomas (approximately 31%), follicular lymphomas (approximately 22%), and the mucosa-associated lymphoid tissue (MALT) lymphomas (approximately 8%). (3,4)

Ahlawat et al (5) report an interesting case of rectal MALT lymphoma. MALT lymphomas (ML) can occur in gastrointestinal as well as extra-gastrointestinal sites. Most of our knowledge of the pathogenesis of these tumors has been from studies of gastric ML. The basic etiology often appears to be an underlying chronic inflammatory state. This could be in the form of chronic infections (6) (for example Helicobacter pylori in approximately 90% of gastric ML cases), autoimmune disorders, (7) or inflammatory bowel disease (and occasional cases of colorectal ML). (8) Another interesting observation is that many of the cases of colorectal ML in the literature have been from Japan--it is unclear if this just represents a reporting bias, or if there is in fact a real difference in various geographic locations. (9)

With respect to the molecular pathogenesis, ML have often been found to be associated with chromosomal translocations, (10) trisomy 3 and 18, (11,12) or the methylation phenotype. (13) The most common translocations are t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1; q32). The t(11;18)(q21;q21) involves the API2 gene (14) and the MALT1 gene. (15,16) The translocation results in a "fusion" or chimeric protein (API2-MALT1), which then activates the NF-[kappa]B pathway resulting in B-cell proliferation and growth. Similarly, the t(1;14), t(14;18), and t(3;14) translocations, bring the BCL10 gene, (17) the MALT1 gene, and the FOXP1 gene (18) under the control of the IGH gene enhancer, resulting in deregulation and overexpression of the BCL10, MALT1, and FOXP1 proteins respectively.

[FIGURE 1 OMITTED]

With regards to the etiology, however, approximately 5 to 10% of gastric ML have been found to be Hpylori negative. (13) In addition, only a small percentage (1-2%) (13,19) of individuals infected with H pylori actually progress to develop malignancy, which highlights that there are other factors that are also involved in the pathogenesis of these tumors. For example, some studies have suggested that individuals with certain specific genotypes, as well as certain select Hpylori genotypes, can be associated with a particularly elevated, (20-22) or decreased risk of ML. (23,24) From the point of view of management, as indicated in the article, (5) most ML have an indolent course. Furthermore, over the past few years there have also been several newer chemotherapeutic agents including fludarabine, (25) cladribine (2CdA), (26) oxaliplatin, (27) rituximab, (28,29) and most recently, bortezomib, (30) which would be helpful to manage tumors that have been resistant to standard first line therapies.

One of the most significant advances in recent years with respect to understanding the genetic basis of these tumors has been the rapidly evolving DNA microarray (or "DNA chip") technology (3,31) (Fig. 2). Traditionally, genetic studies have involved analyzing single genes, or at most a few genes at a time, which alone could take several days or weeks. Considering the fact that there are approximately 25,000 genes in the human genome, (32) it is evident that such an approach is a very labor intensive and time-consuming process. The DNA microarray technology involves several thousands of 'DNA probes,' arranged in an array on a small (approximately 1 to 2 cm) square (Fig. 3), which are then hybridized with mRNA obtained from the patients' tumor samples (an interesting video animation of the same can be seen at the Affymetrix, Inc., web page, http://www.affymetrix.com/corporate/outreach/lesson_plan/educator_resources.affx). Using this approach, expression profiles of several thousand genes can be studied at the same time. Depending on which genes are expressed, tumors have often been found to have unique "molecular signatures" which can help in identifying new classes of tumors ("class discovery"), or to accurately diagnose a tumor ("class prediction"). (33) In addition, in many cases, classifying tumors based on such a molecular basis often helps to identify which tumors are more (or less) likely to respond to various chemotherapeutic agents (pharmacogenomics), (34,35) or to recur (prognostic indicators). (36,37)

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Considering that many of the studies to date have been on gastric ML, future studies should also focus on (1) better characterizing the genetic/environmental basis of the less common extragastric gastrointestinal ML such as colorectal ML (2); investigating any specific reasons for geographical/ethnic variation (3); identifying the infectious agent(s), if any, in colorectal ML (4); investigating the optimal management, as well as preventive strategies (including vaccines (38,39)) for such tumors. Since extragastric sites of ML are less frequent, it may also be beneficial to include cases from multiple centers and accrue a sufficient number of cases, which would be helpful in performing adequately powered studies.

The role of H pylori in gastric disease (including ML) is now firmly established--indeed the recent press release (40) from the Nobel Foundation on October 3rd 2005, read "The Nobel Assembly at Karolinska Insitutet has today decided to award The Nobel Prize in Physiology or Medicine for 2005 jointly to Barry J. Marshall and J. Robin Warren for their discovery of 'the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease'", which was awarded in a ceremony on December 10th 2005. In the forthcoming years, the genomic revolution, that is already currently underway, holds tremendous promise not only to help us better understand the pathogenesis of the various MALT lymphomas, but also to effectively design appropriate therapeutic as well as preventive strategies as we work toward the National Cancer Institute's challenge goal (41) for eliminating the suffering and death due to cancer by the year 2015.

References

1. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Medico-Chirurgical Transactions 1832;17:68-114.

2. Jaffe ES, Harris NL, Stein H, et al, (eds). World Health Organization Classification of Tumours: Pathology and Genetics of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press; 2001.

3. Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology Am Soc Hematol Educ Program 2001:194-220.

4. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997;89:3909-3918.

5. Ahlawat S, Kanbcr Y, Charabaty-Pishvaian A, et al. Primary mucosa-associated lymphoid tissue (MALT) lymphoma occurring in the rectum: a case report and review of the literature South Med J 2006;99:1378-1384.

6. Parsonnet J, Isaacson PG. Bacterial infection and MALT lymphoma. N Engl J Med 2004;350:213-215.

7. Voulgarelis M, Moutsopoulos HM. Lymphoproliferation in autoimmunity and Sjogren's syndrome. Curr Rheumatol Rep 2003;5:317-323.

8. Lenzen R, Borchard F, Lubke H, et al. Colitis ulcerosa complicated by malignant lymphoma: case report and analysis of published works. Gut 1995;36:306-310.

9. Mizushima T, Sugiyama T, Komatsu Y, et al. Clinical relevance of the babA2 genotype of Helicobacter pylori in Japanese clinical isolates. J Clin Microbiol 2001;39:2463-2465.

10. Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005;23:6370-6378.

11. Streubel B, Simonitsch-Klupp I, Mullauer L, et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004;18:1722-1726.

12. Hosaka S, Akamatsu T, Nakamura S, et al. Mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum with chromosomal translocation of the t(11;18)(q21;q21) and an additional aberration of trisomy 3. Am J Gastroenterol 1999;94:1951-1954.

13. Farinha P, Gascoyne RD. Helicobacter pylori and MALT lymphoma. Gastroenterology 2005;128:1579-1605.

14. Dierlamm J, Baens M, Wlodarska I, et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999;93:3601-3609.

15. Akagi T, Motegi M, Tamura A, et al A novel gene, MALTI at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 1999;18:5785-5794.

16. Morgan JA, Yin Y, Borowsky AD, et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res 1999;59:6205-6213.

17. Zhang Q, Siebert R, Yan M, et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 1999;22:63-68.

18. Banham AH, Beasley N, Campo E, et al. The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 2001;61:8820-8829.

19. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347:1175-1186.

20. Lehours P, Menard A, Dupouy S, et al. Evaluation of the association of nine Helicobacter pylori virulence factors with strains involved in lowgrade gastric mucosa-associated lymphoid tissue lymphoma. Infect Immun 2004;72:880-888.

21. Rollinson S, Levene AP, Mensah FK, et al. Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity. Blood 2003;102:1007-1011.

22. Wu MS, Shun CT, Huang SP, et al. Effect of interleukin-1 beta and glutathione S-transferase genotypes on the development of gastric mucosa-associated lymphoid tissue lymphoma. Haematologica 2004;89:1015-1017.

23. Wu MS, Chen LT, Shun CT, et al. Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma. Int J Cancer 2004;110:695-700.

24. Reimer P, Fischbach W, Goebeler ME, et al. Decreased frequency of HLA-B35 in patients with gastric MALT lymphoma. Ann Hematol 2004;83:232-236.

25. Zinzani PL, Stefoni V, Musuraca G, et al. Fludarabine-containing chemotherapy as frontline treatment of nongastrointestinal mucosa-associated lymphoid tissue lymphoma. Cancer 2004;100:2190-2194.

26. Streubel B, Ye H, Du MQ, et al. Translocation t(11;18)(q21;q21) is not predictive of response to chemotherapy with 2CdA in patients with gastric MALT lymphoma. Oncology 2004;66:476-480.

27. Raderer M, Wohrer S, Bartsch R, et al. Phase II study of oxaliplatin for treatment of patients with mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005;23:8442-8446.

28. Conconi A, Martinelli G, Thieblemont C, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 2003;102:2741-2745.

29. Martinelli G, Laszlo D, Ferreri AJ, et al. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23:1979-1983.

30. Bertoni F, Zucca E. State-of-the-art therapeutics: marginal-zone lymphoma. J Clin Oncol 2005;23:6415-6420.

31. Wadlow R, Ramaswamy S. DNA microarrays in clinical cancer research. Curr Mol Med 2005;5:111-120.

32. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 2004;431:931-945.

33. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999;286:531-537.

34. Chin KV, Kong AN. Application of DNA microarrays in pharmacogenomics and toxicogenomics. Pharm Res 2002;19:1773-1778.

35. Chicurel ME, Dalma-Weiszhausz DD. Microarrays in pharmacogenomics-advances and future promise. Pharmacogenomics 2002;3:589-601.

36. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-511.

37. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937-1947.

38. Sutton P, O'Rourke J, Wilson J, et al. Immunisation against Helicobacter felis infection protects against the development of gastric MALT Lymphoma. Vaccine 2004;22:2541-2546.

39. Mueller A, O'Rourke J, Chu P, et al. Protective immunity against Helicobacter is characterized by a unique transcriptional signature. Proc Natl Acad Sci U S A 2003;100:12289-12294.

40. Press Release: The 2005 Nobel Prize in Physiology or Medicine. Available at: http://nobelprize.org/medicine/laureates/2005/press.html. Accessed December 17, 2005.

41. National Cancer Institute. NCI Challenge Goal 2015--Eliminating the Suffering and Death Due to Cancer. Available at: http://www.cancer.gov/aboutnci/2015. Accessed December 8, 2005.

Prathap Bandipalliam, MD

From the Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA.

Reprint requests to Prathap Bandipalliam, MD, Smith #205 Dana-Farber Cancer Institute 44 Binney Street, Boston, MA 02115. Email: [e-mail]

Accepted March 23, 2006.