A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma

Abstract

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. Clin Cancer Res; 24(9); 2044-9. ©2018 AACR.

Figure 1.

The renal cortex is isosmotic to plasma whereas the renal medulla becomes progressively more hypertonic up to ~1200 mOsm/L in the inner medulla. In addition, the medulla becomes progressively more hypoxic with a partial pressure of oxygen (pO₂) as low as 7 mmHg in the inner medulla. These extreme conditions result in red blood cell sickling even in patients with sickle cell trait. Furthermore, the high NaCl concentration in the inner medulla produces DNA double strand breaks and simultaneously inactivates DNA repair pathways that would have otherwise repaired these lesions.

Figure 2.. Proposed steps in renal medullary carcinoma (RMC) pathogenesis.

There are 4 predisposing conditions which interact together: sickle hemoglobinopathy, hypoxia in the renal inner medulla, hypertonicity in the renal medullary interstitium, and presence of low-copy repeats (LCRs) and palindromic AT-rich repeats (PATRRs) within the 22q11.2 locus. The hypoxic microenvironment facilitates the sickling of red blood cells resulting in recurrent regional ischemia and microinfarctions in the renal inner medulla, which reduce the osmolarity in the medullary interstitium. This subsequently reactivates pathways that repair double strand breaks (DSBs) previously induced by hypertonicity (increased NaCl). However, the chronic hypoxia within the renal inner medulla will favor a switch to the more error-prone alternative non-homologous end joining (aNHEJ) repair pathways that are more likely to produce translocations and deletions, particularly in genomic regions such as 22q11.2 which is susceptible to DSB-mediated rearrangements due to the presence of LCRs and PATRRs. Together, these events will result in inactivating translocations and/or deletions of SMARCB1, the tumor suppressor that is always inactivated in RMC. Anatomical differences in blood perfusion will produce more frequent regional ischemia in the right kidney and thus increase the risk of developing RMC in the right vs the left kidney.

Figure 3.

Representation of the location of SMARCB1 within the 22q11.2 region using the UCSC Genome Browser (http://genome.ucsc.edu/). Frequent low-copy repeats (segmental Dups) are noted. The breakpoint cluster region (BCR) gene is in close proximity to SMARCB1.