High prevalence of<i>GPRC5A</i>germline mutations in<i>BRCA1</i>-mutant breast cancer patients

Sokolenko, Anna P.; Bulanova, Daria; Iyevleva, Aglaya G.; Aleksakhina, Svetlana N.; Preobrazhenskaya, Elena V.; Ivantsov, Alexandr O.; Kuligina, Ekatherina Sh.; Mitiushkina, Natalia V.; Suspitsin, Evgeny N.; Yanus, Grigoriy A.; Zaitseva, Olga A.; Yatsuk, Olga S.; Togo, Alexandr V.; Kota, Poojitha; Dixon, JM; Larionov, Alexey; Kuznetsov, Sergey G.; Imyanitov, Evgeny N.

doi:10.1002/ijc.28569

Cited by 31 publications

(30 citation statements)

References 43 publications

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“…PGM1 is known to be induced under hypoxic conditions and promotes cancer cell survival (35). In addition, it has been shown that GPRC5A is a modifier of breast cancer risk in breast cancer (BRCA)-mutation carriers and GPRC5A inactivation negatively affects BRCA1-mediated DNA repair (36). We found that UHRF1 is involved in the up-regulation of SCD1 and SPRY4 but not of PGM1 and GPRC5A.…”

Section: Discussionmentioning

confidence: 76%

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Taniue

Kurimoto

Sugimasa

et al. 2016

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

134

127

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Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domaincontaining protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.A mong the RNA products transcribed from the mammalian genome are numerous long noncoding RNAs (lncRNAs)-that is, RNAs longer than 200 nucleotides with little or no protein-coding potential (1, 2). Many lncRNAs are expressed in a developmentally regulated and cell type-dependent manner (3, 4). Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis, and stem cell pluripotency (5, 6).It has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic regions (2). It has also been shown that many lncRNAs regulate transcription by modulating the activity of transcriptional regulators (1, 6-8). lncRNAs also regulate various posttranscriptional processes, including splicing, transport, translation, and degradation of mRNA. Furthermore, recent studies have shown that a number of lncRNAs play critical roles in tumor development and progression.UHRF1 [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1] is an epigenetic factor that consists of multiple domains (9). UHRF1 regulates transcription by regulating DNA methylation and histone modification. UHRF1 also possesses E3 ubiquitin ligase activity and ubiquitinates histones and DNA methyltransferase 1 (DNMT1), thereby regulating the chromatin structure and stability of DNMT1 (10, 11). UHRF1 plays key roles in multiple biological processes, including proliferation and development. Furthermore, UHRF1 is overexpressed in various tumors, including colon, breast, bladder, prostate, and lung cancers, and plays a critical role in the proliferation and survival of tumor cells (9).In the present study, we attempted to identify lncRNAs criti...

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Section: Discussionmentioning

confidence: 76%

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Taniue

Kurimoto

Sugimasa

et al. 2016

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

134

127

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“…Therefore, rare germ-line defects may act in a cooperative manner for cancer development. In agreement with this notion, our exome sequencing study led to the identification of rare mutation in a GPRC5A gene, which appears to significantly influence the penetrance of BRCA1 gene [135]. Studies on oligogenic inheritance may require the development of novel bioinformatics tools, which allow for robust analysis of gene combinations.…”

Section: Article In Pressmentioning

confidence: 55%

“…Gracia-Aznarez et al [22] and Kiiski et al [21] revealed rare mutations in the FANCM gene, which turned out to be overrepresented in breast cancer cases vs. controls. Arguably, the study of Sokolenko et al [135] is the most successful for the time being: they reported identification of recurrent mutations in the RECQL gene, which occurred approximately 5 times more frequently in patients vs. healthy donors, and were present in 0.69% patients from Poland and in 0.23% BC cases in Canada. Still, the frequency of RECQL germ-line mutations in affected women is manifold lower as compared to "classical" BC genes.…”

Section: Breast Cancermentioning

confidence: 96%

“…However, most of the breast cancer exome studies reported so far failed to discover genes, whose significance is similar to BRCA1, BRCA2, CHEK2, PALB2, etc. [19][20][21][22]25,28,[132][133][134][135][136]. For example, Snape et al [133] subjected to WES 50 patients with familial breast cancer; they composed the list of promising candidates, but did not communicate yet the results of subsequent case-control study or segregation analysis.…”

Section: Breast Cancermentioning

confidence: 98%

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Identification of novel hereditary cancer genes by whole exome sequencing

et al. 2015

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Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

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“…The GPRC5A gene was located on chromosome 12p13-p12.3, and its promoter contained an RA response element to which nuclear retinoid receptors (RAR and RXR) can bind [6]. In recent years, GPRC5A had been receiving increasing attentions as it had been shown to play important roles in human cancers, dysregulation of GPRC5A gene had been associated with several cancers including lung cancer [7], breast cancer [8], and colorectal cancer [9]. In nonsmall cell lung carcinoma, Tao and colleagues [6] reported that the mRNA expression levels of GPRC5A were lower in human lung tumors than in adjacent normal tissues.…”

Section: Introductionmentioning

confidence: 99%

GPRC5A overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer

et al. 2015

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G protein-coupled receptor, family C, group 5, member A (GPRC5A) had received attentions for its role in carcinogenesis and prognostic values in several types of cancer. However, the functional roles of GPRC5A in gastric cancer (GC) had never been elucidated. The expression levels of GPRC5A were detected by real-time quantitative reverse transcription PCR and Western blot in GC tissues and adjacent non-tumor tissues. GPRC5A expression in tissue sections of 106 GC samples was evaluated using immunohistochemistry. The staining results were compared with clinicopathological factors and to the prognosis of GC patients. The mRNA and protein expression levels of GPRC5A in gastric cancer tissues were higher than those in adjacent non-tumor tissues. Positive GPRC5A expression was significantly correlated with larger size of primary tumor, diffuse type (Lauren's classification), deeper serosal invasion, and more lymph node metastasis. In addition, Kaplan-Meier curve analysis demonstrated that GC patients with positive GPRC5A expression had poor prognosis than those with negative GPRC5A expression. GPRC5A expression was identified as an independent factor of the overall survival in GC patients by multivariate Cox analysis. Further, the overall survival difference existed between patients with GPRC5A positive and negative groups in GC patients with lymph node metastasis. Our results suggested that elevated levels of GPRC5A played significant roles in GC progression. GPRC5A could serve as a prognostic biomarker of GC.

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High prevalence ofGPRC5Agermline mutations inBRCA1-mutant breast cancer patients

Cited by 31 publications

References 43 publications

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Identification of novel hereditary cancer genes by whole exome sequencing

GPRC5A overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer

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