TY - JOUR
T1 - A model linking sickle cell hemoglobinopathies and smarcb1 loss in renal medullary carcinoma
AU - Msaouel, Pavlos
AU - Tannir, Nizar M.
AU - Walker, Cheryl Lyn
N1 - Funding Information:
The authors thank Sarah E. Townsend for critical reading of the manuscript and Cora Connor for helpful suggestions on the content. P. Msaouel is supported for this research by the NIHT32 CA009666 and a Conquer Cancer Foundation Young Investigator Award.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney. Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene.
AB - Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney. Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene.
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U2 - 10.1158/1078-0432.CCR-17-3296
DO - 10.1158/1078-0432.CCR-17-3296
M3 - Review article
C2 - 29440190
AN - SCOPUS:85047797844
SN - 1078-0432
VL - 24
SP - 2044
EP - 2049
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -