Approximately 80% of acute myeloid leukemia (AML) patients can achieve complete remission, but around half of them relapse within five years. Defining the mechanism of relapse is essential to improve the prognosis of AML. Recently, a clonal evolution model has been proposed as a mechanism for AML relapse. AML cells constitute a heterogeneous population, and form subclones that acquired new mutations based on the founder clone. Relapse of AML is considered to be derived from clones that could not be killed by the treatment or clones that acquired new mutations during treatment. Theses observation suggest that anti-cancer drug treatment-related DNA damage is associated with AML recurrence.

Fig. 1.

Reactive oxygen species (ROS) are one of the major sources of DNA damage. Several anti-cancer agents produce ROS. For example, doxorubicin, anti-cancer drug for AML, induces 8-oxoguanine (8-OG) production in AML cells via ROS generation. 8-OG is an oxidatively damaged mutagenic base, which causes G:C to T:A transversion mutations in DNA. Recent studies have shown that relapsed AML has more transversion mutations than primary AML. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in the maintenance of genetic stability. We hypothesized that BER polymorphisms affect AML relapse risk, and focused on five major functional BER polymorphisms: OGG1 S326C (rs1052133), MUTYH Q324H (rs3219489), APE1 D148E (rs1130409), XRCC1 R194W (rs1799782), and XRCC1 R399Q (rs25487).

Ninety-four adults with AML who achieved first complete remission were recruited. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse (28.9% vs. 8.9%, odds ratio [OR] = 4.10, 95% confidence interval [CI] = 1.35-12.70, P = 0.01). Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations.

OGG1 is an important DNA repair enzyme that removes 8-OG from genomic DNA, thereby suppressing the G:C to T:A transversion mutation induced by 8-OG. The OGG1 S326C polymorphism is located in a domain that is important for this activity. Previous study has shown that the glycosylase activity of the OGG1-C326 protein is lower than that of OGG1-S326. Therefore, we hypothesized that low OGG1 activity promotes genetic mutation in AML cells, eventually leading to relapse.

In conclusion, our data suggest that OGG1 S326C can be a prognostic factor for AML relapse. To the best of our knowledge, this is the first report about relationship between DNA repair enzyme gene polymorphism and AML relapse. Although further studies of larger populations are necessary to confirm these data, our findings provide novel insights into the relationship between DNA repair and AML relapse.

Nanami Gotoh¹,Tetsuhiro Kasamatsu¹,Hiroshi Handa²,Takayuki Saitoh^1
1Graduate School of Health Sciences, Gunma University, Gunma, Japan
²Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan

Publication

Association between OGG1 S326C CC genotype and elevated relapse risk in acute myeloid leukemia.
Gotoh N, Saitoh T, Takahashi N, Kasamatsu T, Minato Y, Lobna A, Oda T, Hoshino T, Sakura T, Shimizu H, Takizawa M, Handa H, Yokohama A, Tsukamoto N, Murakami H
Int J Hematol. 2018 Sep

Read offline:

Related Articles:

	Defects in mismatch repair increase cancer risk and…Microsatellites are formed by 1-6 nucleotide base pairs that are repeated in direct order 5-50 times. Repetitive DNA including microsatellites are mainly present in non-coding DNA regions that occupy more…
	Is the ACTN3 gene a real “speed gene” in horses?The ACTN3 gene encoding α-actinin-3 in humans is considered to be a key factor in determining the predisposition to short- or long-term exercise (sprint or endurance). In addition, mutations within…
	Epigenetic phenotype diversification helps animals to adapt…There is increasing evidence that epigenetic phenotype variation can contribute to environmental adaptation, speciation and evolution. Epigenetic changes of the phenotype are caused by differences in gene expression rather than…
	A molecular passport authorizes intracellular travel for a…Whether from external environmental factors or spontaneous intracellular processes, the DNA in our cells is under constant bombardment by DNA damage. Because unrepaired DNA damage can cause cell death, our…
	Metformin improves pancreatic cancer and lymphoma outcomes…Type 2 diabetics are at increased risk of cancer in part because of increased insulin in the blood from insulin resistance. Insulin and its related growth factor IGF-1 can stimulate…
	Insight into the needs of thyroid cancer patients before…The thyroid is a butterfly-shaped gland in the neck below the Adam’s apple. It produces hormones that help influence our metabolism and normal development. Over the last 30 years, the…