The Impact of Patient Specific Carcinogen Exposures on TP53 Mutated Acute Myeloid Leukaemia and Other Myeloid Neoplasms
Authors: Liston Katie , Holt Samuel , Buckley Gavin , Mykytiv Vitaliy 
Published: December 2024

Background:

The ICC and the WHO have incorporated TP53 status in the subclassification of a variety of myeloid neoplasms. The development of TP53 mutations is linked with carcinogen exposures such as chemotherapeutic agents, radiation therapy (in therapy-related neoplasms)1 and smoking2. There is a lack of real-world data relating to carcinogen exposures and their relationship with the development of TP53 mutated myeloid neoplasms.

Aims:

To assess the impact of patient specific carcinogenic exposures on the development of TP53 mutated myeloid neoplasms.

Methods:

This was a retrospective observational study. All patients with TP53 mutated AML, MDS or MDS/MPN diagnosed on next generation sequencing in a single centre between 2018-2023 were included. A cohort of patients with TP53 unmutated myeloid neoplasms were also included to create a matched control group. Patients with neoplasms other than AML, MDS or MDS/MPN were excluded. Data extrapolated from patient charts included: prior exposure to chemotherapy, radiation therapy, smoking and alcohol excess (&gt;11 drinks/week females, &gt;17 drinks/week males). Chi square analysis was used to assess for differences between the TP53 mutated and unmutated group (significance p &lt;0.05).

Results:

In total 92 patients were identified. 41 patients were TP53 mutated and 51 patients were TP53 unmutated. The median age at diagnosis in the TP53 group was 68 years. 25 patients were identified with AML, 12 with MDS and 4 with MDS/MPN.

There was no significant difference noted between the TP53 mutated and unmutated group in terms of history of smoking, alcohol excess or prior chemotherapy. There was a significant difference found between groups in terms of history of radiation therapy; TP53 mutated group=19.5%, TP53 unmutated group=4% (p=0.019). A significant difference in mean survival was also noted between the groups (p=0.002).

Missense mutations were the commonest type of TP53 mutation identified (71%). Other mutations included: Stop-gain, Variants of Undetermined Significance (VUS), Frameshift, In-Frame and Splice effect. All patients harboured different variants of the TP53 mutation with the exception of c.743G&gt;A p.Arg248Gln variant which was detected in two different patients. 10 patients developed a second TP53 mutation during treatment. The most common co-occurring mutations were in DNMT3A (5/41) in the TP53 mutated group and in ASXL1 (20/51) in the TP53 unmutated group.

Summary/conclusion:

This study offers real world data on carcinogen exposure in TP53 mutated myeloid neoplasms. In contrast to previously published data there was no significant difference in smoking history between TP53 mutated and unmutated groups. There was also no difference in prior chemotherapy exposure or history of alcohol excess. There was a significant difference between the groups in terms of prior radiation therapy exposure suggesting a link between radiation therapy and the development of TP53 mutated neoplasms which was not observed with prior chemotherapy exposure in these groups. This highlights a degree of heterogeneity in the exposures that qualify as therapy-related in current classification systems. Further studies with larger datasets are required to elucidate the mechanisms underlying the acquisition of TP53 mutations secondary to environmental exposures.

References: Lindsley, R.C. et al. (2015) ‘Acute myeloid leukemia ontogeny is defined by distinct somatic mutations’, Blood, 125(9), pp. 1367-1376. doi:10.1182/blood-2014-11-610543 Bi, X. et al. (2020) ‘Impact of smoking and TP53 mutations in acute myeloid leukemia and myelodysplastic syndromes’, Blood, 136(Supplement 1), pp. 35-35. doi:10.1182/blood-2020-141640