Whole exome sequencing in families with CLL detects a variant in Integrin β 2 associated with disease susceptibility

Goldin, Lynn R.; McMaster, Mary L.; Rotunno, Melissa; Herman, Sarah E. M.; Jones, Kristine; Zhu, Bin; Boland, Joseph F.; Burdett, Laurie; Hicks, Belynda; Ravichandran, Sarangan; Luke, Brian T.; Yeager, Meredith; Fontaine, Laura; Goldstein, Alisa M.; Chanock, Stephen J.; Tucker, Margaret A.; Wiestner, Adrian; Marti, Gerald E.; Caporaso, Neil E.

doi:10.1182/blood-2016-02-697771

Cited by 17 publications

(20 citation statements)

References 9 publications

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“…Mac‐1 is a receptor for the complement 3(CR3), through an interplay with the complement fragment iC3b, having a great influence on complement‐dependent phagocytosis . One study found that in the early adhesive steps of liver metastasis, Mac‐1 mediates the adhesion of neutrophils to cancer cells, and another study found that ITGB2 variant rs2230531 C > T detected by the whole exome sequencing contributed to the susceptibility to chronic lymphocytic leukemia . However, the role of ITGB2 in lung cancer remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Potentially functional genetic variants in the complement‐related immunity gene‐set are associated with non‐small cell lung cancer survival

Qian

Liu

et al. 2018

Intl Journal of Cancer

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The complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody‐based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two‐phase analysis of two independently published genome‐wide association studies (GWASs) for associations between genetic variants in a complement‐related immunity gene‐set and overall survival of non‐small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false‐positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single‐nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single‐locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07–1.40, P = 0.002] and 1.16 (1.07–1.27, 6.45 × 10−4), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival‐associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement‐related immunity genes might be predictors of NSCLC survival, particularly for the short‐term survival, possibly by modulating the expression of genes involved in the host immunity.

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Section: Discussionmentioning

confidence: 99%

Potentially functional genetic variants in the complement‐related immunity gene‐set are associated with non‐small cell lung cancer survival

Qian

Liu

et al. 2018

Intl Journal of Cancer

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“…The variant shows a glutamate to lysine E630K change, which probably impairs CD18 function. The expression of the CD18 variant in patients' B cells is even lower than that of the wild-type form [40]. By contrast, a CLL subgroup of patients harboring trisomy 12 (approximately 16% of CLL patients) show an important increase of LFA-1 and other integrins, associated with high cell proliferation and lymph node infiltration [41] [42].…”

Section: Lfa-1 In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

“…Despite the necessity of CLL B cells to home to lymph nodes and bone marrow, it is not uncommon to observe a lower CD18 expression in B-CLL than that of normal B cells in healthy individuals [35]. Recently, a CD18 variant present in CLL patients has been associated with increased disease susceptibility [40]. The variant shows a glutamate to lysine E630K change, which probably impairs CD18 function.…”

Section: Lfa-1 In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Role of LFA-1 and ICAM-1 in Cancer

Reina

Espel

2017

Preprint

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The lymphocyte function-associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA's role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.Keywords: cancer metastasis; chronic lymphocytic leukemia; exosomes; tumor microenvironment LFA-1 is widely expressed in hematopoietic cells, mediating intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAM), including ICAM-1 (CD54) are common ligands for LFA-1 [1] [2]. The strength of LFA-1 adhesion varies by adjusting the affinity (conformation), the level of LFA-1 clustering and the force applied by the ligand [3] [4] [5]. LFA-1 can adopt different conformations, from a folded low-affinity inactive one to an open active conformation. The stimulation of cells by receptors like the T-cell receptor or chemokine receptors changes the adhesive properties of LFA-1 in a process called "inside-out" signaling that may open the conformation of LFA-1 and expose its ligand-binding site [6]. In addition, it should be noted that the characteristics of the external ligand binding to LFA-1 initiates a signaling cascade in LFA-1 (named "outside-in" signaling), giving rise to various cellular changes [7]. As with other integrins, LFA-1 is not a mere adhesive contact between cells, but it also mediates signals that modulate the growth, differentiation and survival of the cell. LFA-1 participates in the cytotoxic immune response against tumorsThe T cell cytotoxic response against cancer cells starts when the T cell receptor recognizes a specific tumor antigen on the surface of the cancer cell; this is normally followed by delivery of toxic granules that kill the target cell. In the cytolytic response against virus-infected cells, the adhesion between the cytotoxic lymphocyte and the target cell is not strictly dependent on LFA-1, this however is necessary in the cytolytic response to immunogenic tumors [8] [9]. LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by chan...

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“…1 In one of the few studies published to date using this approach, Goldin et al recently reported that a rare variant (rs2230531) within ITGB2 is associated with genetic predisposition to chronic lymphocytic leukemia (CLL). 2 In this study, whole-exome sequencing was performed in a discovery set of 20 high-risk CLL families. Analysis proceeded on a "per family basis," to identify rare (minor allele frequency [MAF] ,1% in population databases), nonsynonymous variants shared in the CLL cases, as well as obligate carriers and non-Hodgkin lymphoma cases.…”

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confidence: 99%

“…In summary, this variant was detected in 6 of 59 CLL families and 3 CLL cases from a clinical cohort, all with a family history of lymphoid malignancy. 2 Integrins are broadly known for their role in cancer 3 ; however, mutations in ITGB2 have not previously been implicated in CLL. Variation in ITGB2 presents as an interesting biological candidate for the genetic susceptibility of CLL.…”

mentioning

confidence: 99%

Evaluating a CLL susceptibility variant in ITGB2 in families with multiple subtypes of hematological malignancies

Blackburn

Marthick

Banks

et al. 2017

Blood

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Whole exome sequencing in families with CLL detects a variant in Integrin β 2 associated with disease susceptibility

Cited by 17 publications

References 9 publications

Potentially functional genetic variants in the complement‐related immunity gene‐set are associated with non‐small cell lung cancer survival

Potentially functional genetic variants in the complement‐related immunity gene‐set are associated with non‐small cell lung cancer survival

Role of LFA-1 and ICAM-1 in Cancer

Evaluating a CLL susceptibility variant in ITGB2 in families with multiple subtypes of hematological malignancies

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