BOSTON – A newly constructed map of the landscape of genetic changes in chronic lymphocytic leukemia (CLL), a type of cancer of the blood and bone marrow that exists in diverse forms and arises from various causes, provides a better understanding of this complex malignancy that could lead to more accurate prognoses for patients, improved diagnostics, and novel treatments. The work is published in Nature Genetics and was conducted by an international collaboration of investigators, including teams from the Mass General Cancer Center, the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard.
CLL exists as either a slowly or rapidly growing cancer and has been linked with certain genetic mutations, but it has yet to be fully characterized. Previous analyses have provided only fragments of a CLL “map”, each focusing on particular types of patients or limited data. To provide a more thorough understanding of the biological underpinnings of CLL and its molecular subtypes, scientists set out to construct a map from the largest CLL dataset to date.
To build the CLL map, the team analyzed variations in genetic sequences, gene expression patterns, and chemical modifications to DNA—or genomic, transcriptomic, and epigenomic data—from 1,148 patients. “Such a CLL map could eventually be leveraged in the clinic, wherein the genomic features of new patients can be compared with the treatments and outcomes of patients with similar genetic profiles,” says co–senior and co–corresponding author Catherine Wu, MD, chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute and professor of Medicine at Harvard Medical School. “This profiling could potentially help more accurately tailor prognosis and treatment of a new patient based on their particular molecular features, getting closer to precision medicine.”
The scientists identified 202 genes (109 of which were novel) that when mutated could potentially drive CLL, and they refined the characterization of subtypes of CLL with distinct genomic characteristics and prognoses. Beyond genetic sequences, the expression patterns of certain genes further subcategorized CLL and provided valuable prognostic information. “Our study has revealed that the genetic and biologic landscape of CLL is more complex than previously appreciated,” says co–senior and co–corresponding author Gad Getz, PhD, director of Bioinformatics at the Mass General Cancer Center and director of the Cancer Genome Computational Analysis group at the Broad Institute.
Patients’ clinical outcomes were associated with a combination of genomic, transcriptomic, and epigenomic features—so that integrating these data could predict a patient’s likelihood of experiencing remission versus developing more advanced cancer.
“We are releasing a CLL map ‘portal’ that is based on the CLL map and will be an interactive website for translational researchers to use as a resource for further investigation—such as learning more about the different drivers and subtypes of CLL,” says Getz.
The study was also led by José I. Martín-Subero (IDIBAPS), Xose S. Puente (Universidad de Oviedo), and Elias Campo (IDIBAPS and Hospital Clinic of Barcelona) from Spain; and Stephan Stilgenbauer (Ulm University) from Germany.
Additional study authors include the co–first authors Binyamin A. Knisbacher, Ziao Lin, Cynthia K. Hahn, Ferran Nadeu, and Martí Duran-Ferrer, alongside many additional co-authors: Kristen E. Stevenson, Eugen Tausch, Julio Delgado, Alex Barbera-Mourelle, Amaro Taylor-Weiner, Pablo Bousquets-Muñoz, Ander Diaz-Navarro, Andrew Dunford, Shankara Anand, Helene Kretzmer, Jesus Gutierrez-Abril, Sara López-Tamargo, Stacey M. Fernandes, Clare Sun, Mariela Sivina, Laura Z. Rassenti, Christof Schneider, Shuqiang Li, Laxmi Parida, Alexander Meissner, François Aguet, Jan A. Burger, Adrian Wiestner, Thomas J. Kipps, Jennifer R. Brown, Michael Hallek, Chip Stewart, and Donna S. Neuberg.
This work was supported by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham health care system.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute is the only hospital in the nation to be ranked in the top 5 in the U.S. News & World Report’s Best Cancer Hospitals list in both adult and pediatric care. Dana-Farber’s mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement and equity, and advocacy. We provide the latest in cancer care for adults through Dana-Farber Brigham Cancer Center and for children through Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Dana-Farber is dedicated to a unique and equal balance between cancer research and care, translating the results of discovery into new treatments for patients locally and around the world.
Method of Research
Subject of Research
Molecular map of chronic lymphocytic leukemia and its impact on outcome
Article Publication Date
C.J.W. receives research support from Pharmacyclics. E.C. has been a consultant for Illumina. G.G. receives research funds from IBM and Pharmacyclics; and is an inventor on patent applications related to SignatureAnalyzer-GPU. S.S. reports honoraria for consultancy, advisory board membership, speaker honoraria, research grants and travel support from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis. C.J.W., G.G., B.A.K., Z.L. and C.K.H. are inventors on a patent “Compositions, panels, and methods for characterizing chronic lymphocytic leukemia” (PCT/US21/45144). The following conflicts are unrelated to the CLLmap project: F.N. has received honoraria from Janssen for speaking at educational activities. E.T. declares research support by Abbvie and Roche; Advisory Boards and Speakers Bureau for Janssen, Abbvie and Roche. A.W. received research funding from Pharmacyclics, Acerta, Merck, Verastem, Genmab, Nurix. J.R.B. has served as a consultant for Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Novartis, Pfizer, Rigel; received research funding from Gilead, Loxo/Lilly, Verastem/SecuraBio, Sun, TG Therapeutics; and served on the data safety monitoring committee for Invectys. J.A.B. received research support from AstraZeneca, BeiGene, Gilead, and Pharmacyclics; travel and speaker honoraria from Janssen. X.S.P. is a cofounder of and holds an equity stake in DREAMgenics. C.J.W. holds equity in BioNTech, Inc.. E C. has been a consultant for Takeda and NanoString Technologies; has received honoraria from Janssen and Roche for speaking at educational activities; and is an inventor on a Lymphoma and Leukemia Molecular Profiling Project patent "Method for subtyping lymphoma subtypes by means of expression profiling" (PCT/US2014/64161). G.G. is an inventor on patent applications related to MSMuTect, MSMutSig, MSIDetect, and POLYSOLVER; and is a founder and consultant of and holds privately held equity in Scorpion Therapeutics. The other authors have no competing interests to declare.