Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia

Abstract

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.

Deficiency of ribosomal protein S26, which is mutated in a subset of patients with Diamond Blackfan anemia, impairs erythroid differentiation

“…Some reports suggest that mutations in distinct RP genes lead to differences in erythroid phenotypes ( Moniz et al, 2012 ; Gastou et al, 2017 ) and predisposition to cancer ( Lipton et al, 2022 ). In particular, it is interesting to note that among the most prevalent DBA genes, RPS26 is the only one that has never been found mutated in patients that developed cancer or myelodysplastic syndrome ( Lipton et al, 2022 ). To explain this peculiarity, it has been hypothesized that RPS26-deficient 40S subunits found in RPS26 -mutated DBA patients could selectively translate subsets of mRNAs with a protective function against cancer development ( Lipton et al, 2022 ).…”

“…In particular, it is interesting to note that among the most prevalent DBA genes, RPS26 is the only one that has never been found mutated in patients that developed cancer or myelodysplastic syndrome ( Lipton et al, 2022 ). To explain this peculiarity, it has been hypothesized that RPS26-deficient 40S subunits found in RPS26 -mutated DBA patients could selectively translate subsets of mRNAs with a protective function against cancer development ( Lipton et al, 2022 ). Recent work has shown that yeast Rps26 exhibits some unique properties among ribosomal proteins, since stresses like high Na + or H + concentrations cause the release of Rps26 from the ribosome via binding with the chaperone Tsr2 ( Ferretti et al, 2017 ; Yang and Karbstein, 2022 ).…”

“…Here, we turn to another ribosomal protein affected in DBA patients, RPS26. The RPS26 gene is one of the most frequently mutated gene in DBA patients and is found mutated in 5.3–-11.6% of cases ( Doherty et al, 2010 ; Smetanina et al, 2015 ; van Dooijeweert et al, 2018 ; Quarello et al, 2020 ; Volejnikova et al, 2020 ; Lipton et al, 2022 ). RPS26, like other ribosomal proteins affected in DBA, is required for ribosome biogenesis, specifically for the maturation of 40S ribosomal subunits.…”

“…DBA is due to the inability of erythroid progenitors to proceed with erythroid maturation, while the other bone marrow cell lineages generally show normal counts. The clinical manifestations are heterogeneous and include red cell aplasia, congenital malformations and cancer predisposition, both to hematological malignancies and solid tumors ( Vlachos et al, 2018 ; Lipton et al, 2022 ). Corticosteroids are a first-line therapy for the anemia in DBA and are effective in at least half the cases.…”

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19

“…Colorectal cancer and osteogenic sarcoma are the most prevalent solid tumors in patients with DBA, and the Diamond Blackfan Anemia Registry (DBAR) has recently released early screening guidelines for CRC (Lipton et al, 2021b). At the present time, the median age for developing CRC in the setting of DBA is 41 years, though based on only nine patients (Lipton et al, 2021a). While the two individuals who developed CRC in our family do not meet the definition of early onset CRC (age of diagnosis <50 years), they still developed CRC prior to the median age in the general population of 66 years (Hofseth et al, 2020;Siegel et al, 2020).…”