Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution

Francesco D'Amore, Eric Chan, Javeed Iqbal, Huimin Geng, Ken Young, Li Xiao, Michelle M. Hess, Warren G. Sanger, Lynette M Smith, Carsten Wiuf, Oskar Hagberg, Kai Fu, Wing C. Chan, Bhavana J Dave

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Abstract

Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome. Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed. Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances. Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.

Original languageEnglish (US)
Pages (from-to)7180-7187
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number22
DOIs
StatePublished - Nov 15 2008

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Clonal Evolution
Follicular Lymphoma
Biopsy
Clone Cells
Karyotype
Cytogenetics
Chromosome Breakage
Molecular Evolution
Cytogenetic Analysis
Chromosome Aberrations
Disease-Free Survival
Disease Progression
Neoplasms
Research Design
Databases
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution. / D'Amore, Francesco; Chan, Eric; Iqbal, Javeed; Geng, Huimin; Young, Ken; Xiao, Li; Hess, Michelle M.; Sanger, Warren G.; Smith, Lynette M; Wiuf, Carsten; Hagberg, Oskar; Fu, Kai; Chan, Wing C.; Dave, Bhavana J.

In: Clinical Cancer Research, Vol. 14, No. 22, 15.11.2008, p. 7180-7187.

Research output: Contribution to journalArticle

D'Amore, Francesco ; Chan, Eric ; Iqbal, Javeed ; Geng, Huimin ; Young, Ken ; Xiao, Li ; Hess, Michelle M. ; Sanger, Warren G. ; Smith, Lynette M ; Wiuf, Carsten ; Hagberg, Oskar ; Fu, Kai ; Chan, Wing C. ; Dave, Bhavana J. / Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 22. pp. 7180-7187.
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abstract = "Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome. Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed. Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26{\%}) and sequential biopsies (63{\%}) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances. Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.",
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AU - D'Amore, Francesco

AU - Chan, Eric

AU - Iqbal, Javeed

AU - Geng, Huimin

AU - Young, Ken

AU - Xiao, Li

AU - Hess, Michelle M.

AU - Sanger, Warren G.

AU - Smith, Lynette M

AU - Wiuf, Carsten

AU - Hagberg, Oskar

AU - Fu, Kai

AU - Chan, Wing C.

AU - Dave, Bhavana J

PY - 2008/11/15

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N2 - Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome. Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed. Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances. Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.

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