Revertant somatic mosaicism as a cause of cancer

Abstract

Revertant (somatic) mosaicism is a spontaneous correction of a causative mutation in patients with congenital diseases. A relatively frequent event, revertant mosaicism may bring favorable outcomes that ameliorate disorders, and is therefore called "natural gene therapy." However, it has been revealed recently that "overcorrection" of inherited bone marrow failure in patients with sterile alpha motif domain containing 9 (SAMD9)/9L syndromes by revertant mosaicism induces myelodysplastic syndrome (MDS) with monosomy 7 that occasionally proceeds to acute myelogenous leukemia (AML). In this review, we interpret very complex mechanisms underlying MDS/AML in patients with SAMD9/9L syndromes. This includes multiple myeloid tumor suppressors on the long arm of chromosome 7, all of which act in a haploinsufficient fashion, and a difference in sensitivity to interferon between cells carrying a mutation and revertants. Overcorrection of mutants by somatic mosaicism is likely a novel mechanism in carcinogenesis.

Keywords: SAMD9/9L syndromes; haploinsufficiency; revertant mosaicism; somatic mutation; tumor suppressors.

FIGURE 1

Two types of tumor suppressors. Classical recessive tumor‐suppressor genes (upper panel), such as RB, TP53, PTEN, and BRCA. Cancer progression occurs only when all alleles on each gene lose their function by deletion, mutation or methylation. This is a rare event, but once it happens this would have a substantial effect on carcinogenesis. By contrast, tumor suppressor genes acting in a haploinsufficient (h/i) manner lose their function by lacking just one gene (lower panel). This will occasionally happen and damage is expected to be small

FIGURE 2

Deletion of a chromosome region that contains many haploinsufficient (h/i) tumor suppressor genes would greatly increase cancer progression. Because considerable damage would be caused by even a partial deletion of the region, the deleted area in each patient would vary

FIGURE 3

Haploinsufficient (h/i) myeloid tumor suppressor genes on 7q

FIGURE 4

A scheme of myelodysplastic syndrome (MDS) carrying ‐7/del(7q). In patients with SAMD9/9L syndromes, bone marrow cells with SAMD9/9L^+/− (revertants) show a high sensitivity to growth factors and a low sensitivity to (the suppressive effects of) interferon (IFN)γ. In addition, surrounding bone marrow cells (SAMD9/9L^+/mut) have a high sensitivity to IFNγ. As a result, the rapid expansion of a ‐7/del(7q) clone causes an “overcorrection,” leading to MDS. This mechanism would be partially applied to sporadic MDS patients with ‐7/del(7q) in old age