Genome-Wide Testing of Putative Functional Exonic Variants in Relationship with Breast and Prostate Cancer Risk in a Multiethnic Population

Haiman, Christopher A.; Han, Ying; Feng, Yang; Xia, Lucy; Hsu, Chris; Sheng, Xin; Pooler, Loreall; Patel, Yesha; Kolonel, Laurence N.; Carter, Erin; Park, Karen; Marchand, Loı̈c Le; Berg, David Van Den; Henderson, Brian E.; Stram, Daniel O.

doi:10.1371/journal.pgen.1003419

Cited by 71 publications

(74 citation statements)

References 48 publications

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“…SLC transporters have been implicated in some solid malignancies; here we report the involvement of SLC transporters in B-CLLs. Exonic variants in SLC16A6 were found to be strongly correlated with disease heritability in breast cancer (17). A recent genome-wide association study reported genetic variants in SLC35D2 and their role in non-small cell lung cancer (18).…”

Section: Discussionmentioning

confidence: 99%

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

Sandhu

Fassan

Volinia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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miR-17∼92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss-and gain-of-function studies have revealed the role of miR-17∼92 in heart, lung, and B-cell development and in Mycinduced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available. To determine whether miR-17∼92-overexpression induces lymphomagenesis/leukemogenesis, we generated a B-cell-specific transgenic mouse model with targeted overexpression of this cluster in B cells. The miR-17∼92 overexpression was driven by the Eμ-enhancer and Ig heavy-chain promoter, and a 3′ GFP tag was added to the transgene to track the miR expression. Expression analysis using Northern Blot and quantitative RT-PCR confirmed 2.5-to 25-fold overexpression of all six miRs in the transgenic mice spleens as compared with spleens from wild-type mice. Eμ-miR-17∼92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of ∼80% (49% splenic B-cell lymphoproliferative disease, 28% lymphoma). At this stage mice exhibited severe splenomegaly with abnormal B-cell-derived white pulp expansion and enlarged lymph nodes. Interestingly, we found three classes of B-cell lymphomas/leukemias at varying grades of differentiation. These included expansion of CD19 + and CD5 + double-positive B cells similar to the aggressive form of human B-cell chronic lymphocytic leukemia, B220 + CD43 + B1-cell proliferation, and a CD19 + aggressive diffuse large B-cell lymphoma-like disease, as assessed by flow cytometry and histopathological analysis. miR-17∼92 cluster | animal model | SLC/ABC transporters M icroRNAs (miRs) are 21-to 22-nucleotide-long noncoding RNA molecules that regulate the expression of multiple cellular genes, and their dysregulation is involved in many human diseases including cancer. The MiR-17∼92 cluster frequently is up-regulated in several different malignancies including diffuse large B-cell lymphoma (DLBCL) (1) and lung cancer (2, 3). The MiR-17∼92 cluster is encoded by the chromosome 13q31 locus in humans and the 14qE4 locus in mice. This genomic region is amplified in DLBCLs and several other tumors (reviewed in ref. 4). The cluster consists of six miRs (miR-17, 18a, 19a, 20a, 19b-1, and 92a-1) and has two paralogs in the genome, miR-106a∼363 and miR-106b∼25, proposed to have arisen through series of duplication and deletion events during vertebrate evolution (5).The first suggestion for its possible role in oncogenesis came from the study in Eμ-Myc mice in which enforced expression of miR-17∼92 was shown to accelerate B-cell tumor development (6). An additional study that investigated the role of miR-17∼92 in mice by driving its overexpression under the human CD2 promoter in both B and T cells found that mice overexpressing the miR-17∼92 clust...

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Section: Discussionmentioning

confidence: 99%

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

Sandhu

Fassan

Volinia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…However, these types of mutations are less common, requiring large sample sizes to detect as well. Meanwhile, while other less common or rare variants may have strong effect sizes, it is not currently clear if this is the case as suggested by recent results in breast and prostate cancer (Haiman et al 2013).…”

Section: Powermentioning

confidence: 93%

Gene-Environment Interactions in Human Health

Mechanic

Hutter

2015

Molecular and Integrative Toxicology

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Risk of most complex diseases is determined by a combination of environmental and genetic factors. By studying gene-environment interactions, it may be possible to describe disease mechanisms, discover novel genetic variants associated with disease, better understand heterogeneity between populations, identify populations with higher risk from exposure, and target preventive and therapeutic interventions. However, there are several challenges to the study of gene-environment interactions. As technologies and analytical tools improve, opportunities to better understand the complex interplay between genes and environment may result in improved insights in disease and treatment outcomes.

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“…Several recent studies have focused on the genetics and genomics of prostate cancer in AA men (2–5). However, no studies have used whole genome sequencing (WGS) to describe genome-wide somatic mutations in prostate tumors from AA patients.…”

Section: Introductionmentioning

confidence: 99%

Mutational Landscape of Aggressive Prostate Tumors in African American Men

et al. 2016

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Prostate cancer is the most frequently diagnosed and second most fatal non-skin cancer among men in the United States. African American men are two times more likely to develop and die of prostate cancer compared with men of other ancestries. Previous whole genome or exome tumor sequencing studies of prostate cancer have primarily focused on men of European ancestry. In this study, we sequenced and characterized somatic mutations in aggressive (Gleason ≥7, stage ≥T2b) prostate tumors from 24 African American patients. We describe the locations and prevalence of small somatic mutations (up to 50 bases in length), copy number aberrations, and structural rearrangements in the tumor genomes compared with patient-matched normal genomes. We observed several mutation patterns consistent with previous studies, such as large copy number aberrations in chromosome 8 and complex rearrangement chains. However, TMPRSS2-ERG gene fusions and PTEN losses occurred in only 21% and 8% of the African American patients, respectively, far less common than in patients of European ancestry. We also identified mutations that appeared specific to or more common in African American patients, including a novel CDC27-OAT gene fusion occurring in 17% of patients. The genomic aberrations reported in this study warrant further investigation of their biological significance in the incidence and clinical outcomes of prostate cancer in African Americans.

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Genome-Wide Testing of Putative Functional Exonic Variants in Relationship with Breast and Prostate Cancer Risk in a Multiethnic Population

Cited by 71 publications

References 48 publications

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

Gene-Environment Interactions in Human Health

Mutational Landscape of Aggressive Prostate Tumors in African American Men

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