Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

1. Sílvia Beà^a,¹,
2. Rafael Valdés-Mas^b,
3. Alba Navarro^a,
4. Itziar Salaverria^a,
5. David Martín-Garcia^a,
6. Pedro Jares^a,
7. Eva Giné^a,
8. Magda Pinyol^a,
9. Cristina Royo^a,
10. Ferran Nadeu^a,
11. Laura Conde^a,
12. Manel Juan^a,
13. Guillem Clot^a,
14. Pedro Vizán^c,
15. Luciano Di Croce^c,
16. Diana A. Puente^b,
17. Mónica López-Guerra^a,
18. Alexandra Moros^a,
19. Gael Roue^a,
20. Marta Aymerich^a,
21. Neus Villamor^a,
22. Lluís Colomo^a,
23. Antonio Martínez^a,
24. Alexandra Valera^a,
25. José I. Martín-Subero^a,
26. Virginia Amador^a,
27. Luis Hernández^a,
28. Maria Rozman^a,
29. Anna Enjuanes^a,
30. Pilar Forcada^d,
31. Ana Muntañola^d,
32. Elena M. Hartmann^e,
33. María J. Calasanz^f,
34. Andreas Rosenwald^e,
35. German Ott^g,
36. Jesús M. Hernández-Rivas^h,
37. Wolfram Klapperⁱ,
38. Reiner Siebert^j,
39. Adrian Wiestner^k,
40. Wyndham H. Wilson^l,
41. Dolors Colomer^a,
42. Armando López-Guillermo^a,
43. Carlos López-Otín^b,²,
44. Xose S. Puente^b,¹,², and
45. Elías Campo^a,¹,²

Author Affiliations

1. Edited* by Louis M. Staudt, National Institutes of Health, Bethesda, MD, and approved September 19, 2013 (received for review August 7, 2013)

Significance

This is a comprehensive whole-genome/whole-exome analysis of mantle cell lymphoma (MCL). We sequenced 29 MCL cases and validated the findings by target sequencing of 172 additional tumors. We identified recurrent mutations in genes regulating chromatin modification and genes such as NOTCH2 that have a major impact on clinical outcome. Additionally, we demonstrated the subclonal heterogeneity of the tumors already at diagnosis and the modulation of the mutational architecture in the progression of the disease. The identification of new molecular mechanisms may open perspectives for the management of MCL patients.

Abstract

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

• next-generation sequencing
• cancer genetics
• cancer heterogeneity

Footnotes

• ¹To whom correspondence may be addressed. E-mail: ecampo@clinic.ub.es, sbea@clinic.ub.es, or xspuente@uniovi.es.
• ²C.L.-O., X.S.P., and E.C. contributed equally to this work.

• Author contributions: S.B., C.L.-O., X.S.P., and E.C. designed research; S.B., R.V.-M., A.N., I.S., D.M.-G., P.J., M.P., C.R., F.N., L. Conde, M.J., P.V., L.D.C., D.A.P., M.L.-G., A. Moros, G.R., L. Colomo, A. Martínez, A.V., J.I.M.-S., V.A., L.H., A.E., R.S., and E.C. performed research; P.V., L.D.C., M.A., P.F., A. Muntañola, E.M.H., A.R., G.O., J.M.H.-R., W.K., R.S., A.W., W.H.W., and D.C. contributed new reagents/analytic tools; S.B., R.V.-M., A.N., I.S., D.M.-G., P.J., E.G., M.P., C.R., M.J., G.C., G.R., N.V., J.I.M.-S., M.R., M.J.C., R.S., D.C., A.L.-G., C.L.-O., X.S.P., and E.C. analyzed data; and S.B., C.L.-O., X.S.P., and E.C. wrote the paper.
• The authors declare no conflict of interest.
• *This Direct Submission article had a prearranged editor.
• Data deposition: Next-generation sequencing data have been deposited at the European Genome-Phenome Archive under accession no. EGAS00001000510. Affymetrix SNP6.0 array and HU133+2.0 gene expression data have been deposited at Gene Expression Omnibus (GEO) under accession nos. GSE46969 and GSE36000, respectively.
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1314608110/-/DCSupplemental.

Freely available online through the PNAS open access option.