Abstract
Chronic lymphocytic leukemia (CLL) is a very common and mostly incurable B-cell malignancy. Recent studies revealed high interpatient mutational heterogeneity and worsened therapy response and survival of patients with complex genomic aberrations. In line with this, a better understanding of the underlying mechanisms of specific genetic aberrations would reveal new prognostic factors and possible therapeutic targets. It is known that chromosomal rearrangements including DNA insertions often play a role during carcinogenesis. Recently it was reported that bacteria (microbiome)–human lateral gene transfer occurs in somatic cells and is enriched in cancer samples. To further investigate this mechanism in CLL, we analyzed paired-end RNA sequencing data of 45 CLL patients and 9 healthy donors, in which we particularly searched for bacterial DNA integrations into the human somatic genome. Applying the Burrows–Wheeler aligner (BWA) first on a human genome and then on bacterial genome references, we differentiated between sequencing reads mapping to the human genome, to the microbiome or to bacterial integrations into the human genome. Our results indicate that CLL samples featured bacterial DNA integrations more frequently (approx. two-fold) compared to normal samples, which corroborates the latest findings in other cancer entities. Moreover, we determined common integration sites and recurrent integrated bacterial transcripts. Finally, we investigated the contribution of bacterial integrations to oncogenesis and disease progression.
Highlights
Chronic lymphocytic leukemia (CLL) is a very common B-cell malignancy that mostly affects elderly people [1]
We for the first time analyzed the load and nature of bacterial integrations in chronic lymphocytic leukemia patients using RNA sequencing data and stratified patients according to lateral gene transfer (LGT) events and clinical parameters
A high integration rate was detected in classswitched memory B cells, showing that LGT may increase with the lifespan of a cell and with high activity of the DNA repair machinery required for immunoglobulin class-switch recombination
Summary
Chronic lymphocytic leukemia (CLL) is a very common B-cell malignancy that mostly affects elderly people [1]. CLL patients show a vastly heterogeneous mutational profile, comprising a high number of passenger and driver mutations, which forward clonal evolution and the course of disease [2,3]. Several somatic mutations and chromosomal aberrations were identified as prognostic factors, and are being used in clinics for therapy choice. IGHV mutated patients have a better prognosis and respond better to fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy, which leads to prolonged progression-free survival [4,5]. Mutations in TP53 and ATM genes or complex chromosomal alterations such as del17q, del11q and tri correspond with worsened prognosis and survival [2,3]. A complex karyotype (≥3 distinct chromosomal abnormalities) leads to impaired therapy response [6]. Duplications and translocations, integrations of foreign DNA represent another type of genomic aberration that can influence carcinogenesis. Various transposon types are well described and are known to contribute to oncogenesis once they become mobile
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