Germline Mutations in<i>HOXB13</i>and Prostate-Cancer Risk

Ewing, Charles M.; Ray, Anna M.; Lange, Ethan M.; Zuhlke, Kimberly A.; Robbins, Christiane M.; Tembe, Waibhav; Wiley, Kathleen E.; Isaacs, Sarah D.; Johng, Dorhyun; Wang, Yunfei; Bizon, Chris; Yan, Guifang; Gielzak, Marta; Partin, Alan W.; Shanmugam, Vijayalakshmi; Izatt, Tyler; Sinari, Shripad; Craig, David W.; Zheng, S. Lilly; Walsh, Patrick C.; Montie, James E.; Xu, Jianfeng; Carpten, John D.; Isaacs, William B.; Cooney, Kathleen A.

doi:10.1056/nejmoa1110000

Cited by 571 publications

(550 citation statements)

References 33 publications

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“…HOXB13 also interacts with the androgen receptor and regulates the cellular response to androgen 51 . In addition, germline mutations of HOXB13 significantly increase risk of hereditary prostate cancer through unknown mechanisms 52 . However, further studies discounted the intriguing possibility that mutation of HOXB13 alters its interaction with NKX3.1 (CCY & DAW, unpublished observation).…”

Section: Resultsmentioning

confidence: 99%

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Yang

Chung²,

et al. 2014

F1000Res

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NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.

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Section: Resultsmentioning

confidence: 99%

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Yang

Chung²,

et al. 2014

F1000Res

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“…3 The mutation accounts for approximately 4% to 5% of prostate cancer in families, Dr. Cooney notes, adding that she believes there are more rare mutations in hereditary prostate cancer that have yet to be discovered.…”

Section: Additional Researchmentioning

confidence: 99%

ASCO, AACR issue joint response to proposed FDA tobacco rule

Printz¹

2014

Cancer

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“…A G84E mutation was identified in four of the linked pedigrees and this same mutation and others in the HOXB13 gene were identified in additional families. [11][12][13] The G84E mutation is significantly associated with disease in men with a family history and/ or early disease onset. The HOXB13 gene binds to the androgen receptor and plays a role in prostate development.…”

Section: Family History and Familial Pcamentioning

confidence: 99%

Genetics and genomics of prostate cancer

Dean¹,

Li²

2013

Asian J Androl

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Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.

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Germline Mutations inHOXB13and Prostate-Cancer Risk

Cited by 571 publications

References 33 publications

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

ASCO, AACR issue joint response to proposed FDA tobacco rule

Genetics and genomics of prostate cancer

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