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Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.

ABSTRACT: Pretherapy patients with chronic lymphocytic leukemia (CLL) from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q-, and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected anomalies, and their number per participant has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with those from a previous study of more than 50,000 participants from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition of the anomalies also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA participants, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA participants, thus identifying genomic changes that may be unique to symptomatic stages of CLL.

SUBMITTER: Laurie CC

PROVIDER: S-EPMC4074414 | biostudies-literature | 2014 Jan-Feb

REPOSITORIES: biostudies-literature

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Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.

Laurie Cathy C CC Laurie Cecelia A CA Smoley Stephanie A SA Carlson Erin E EE Flinn Ian I Fridley Brooke L BL Greisman Harvey A HA Gribben John G JG Jelinek Diane F DF Nelson Sarah C SC Paietta Elisabeth E Schaid Dan D Sun Zhuoxin Z Tallman Martin S MS Weinshilboum Richard R Kay Neil E NE Shanafelt Tait D TD

Cancer genetics 20140117 1-2

Pretherapy patients with chronic lymphocytic leukemia (CLL) from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q-, and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected anomalies, and their number per participant has a significant effect on progression-free survival after adjusting for the effects of 17p ...[more]

PMID: 24613276

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Project description:BackgroundThe presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about associations with presence of non-chromosomal anomalies.MethodsRecords of children diagnosed with cancer at <20 years of age during 1984-2013 in Washington State cancer registries were linked to their birth certificates (N = 4,105). A comparison group of children born in the same years was identified. Congenital anomalies were assessed from birth records and diagnosis codes in linked hospital discharge data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for cancer, and for specific cancer types in relation to the presence of any anomaly and specific anomalies.ResultsHaving any congenital anomaly was associated with an increased risk of childhood cancer (OR: 1.46, 95% CI 1.28-1.65). Non-chromosomal anomalies were also associated with increased childhood cancer risk overall (OR: 1.35; 95% CI: 1.18-1.54), and with increased risk of several cancer types, including neuroblastoma, renal, hepatoblastoma, soft-tissue sarcoma, and germ cell tumors. Increasing number of non-chromosomal anomalies was associated with a stronger risk of childhood cancer (OR for 3+ anomalies: 3.11, 95% CI: 1.54-6.11). Although central nervous system (CNS) anomalies were associated with CNS tumors (OR: 6.05, 95% CI 2.75-13.27), there was no strong evidence of other non-chromosomal anomalies being specifically associated with cancer occurring in the same organ system or anatomic location.ConclusionsNon-chromosomal anomalies increased risk of several cancer types. Additionally, we found that increasing number of non-chromosomal anomalies was associated with a stronger risk of cancer. Pooling similar data from many regions would increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer.

Project description:The importance of the tumor microenvironment in chronic lymphocytic leukemia is widely accepted. Nevertheless, the understanding of the complex interplay between the various types of bystander cells and chronic lymphocytic leukemia cells is incomplete. Numerous studies have indicated that bystander cells provide chronic lymphocytic leukemia-supportive functions, but it has also become clear that chronic lymphocytic leukemia cells actively engage in the formation of a supportive tumor microenvironment through several cross-talk mechanisms. In this review, we describe how chronic lymphocytic leukemia cells participate in this interplay by inducing migration and tumor-supportive differentiation of bystander cells. Furthermore, chronic lymphocytic leukemia-mediated alterations in the interactions between bystander cells are discussed. Upon bystander cell interaction, chronic lymphocytic leukemia cells secrete cytokines and chemokines such as migratory factors [chemokine (C-C motif) ligand 22 and chemokine (CC motif) ligand 2], which result in further recruitment of T cells but also of monocyte-derived cells. Within the tumor microenvironment, chronic lymphocytic leukemia cells induce differentiation towards a tumor-supportive M2 phenotype of monocyte-derived cells and suppress phagocytosis, but also induce increased numbers of supportive regulatory T cells. Like other tumor types, the differentiation of stromal cells towards supportive cancer-associated fibroblasts is critically dependent on chronic lymphocytic leukemia-derived factors such as exosomes and platelet-derived growth factor. Lastly, both chronic lymphocytic leukemia and bystander cells induce a tolerogenic tumor microenvironment; chronic lymphocytic leukemia-secreted cytokines, such as interleukin-10, suppress cytotoxic T-cell functions, while chronic lymphocytic leukemia-associated monocyte-derived cells contribute to suppression of T-cell function by producing the immune checkpoint factor, programmed cell death-ligand 1. Deeper understanding of the active involvement and cross-talk of chronic lymphocytic leukemia cells in shaping the tumor microenvironment may offer novel clues for designing therapeutic strategies.

Dataset Information

Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.

Publications

Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.

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