Abstract P2-02-02: Clinical significance of TP53 mosaic mutations uncovered in constitutional genetic testing
Authors: Deucher A , Lincoln S , Sorenson J 
Published: March 2017

Background: Mosaic findings (mutations outside of the expected 50:50 allele ratio) are often detected in the course of routine constitutional genetic testing due to the high sensitivity of next-generation sequencing (NGS) technologies. The significance of these findings is however often unclear. They can result from constitutional mosaicism secondary to an early embryological event, an acquired somatic mutation in hematopoietic cells, a technical artifact, or (less likely) a reversion event. Studies have shown that clonal hematopoiesis increases with age, seen in up to 10% and 25% of individuals 65 and 90 years of age, respectively. Additional studies have demonstrated expansion of TP53 mutations in peripheral blood cells following chemotherapy administration. We therefore wanted to investigate the potential clinical significance of mosaic mutations found in the peripheral blood in samples submitted for hereditary cancer testing with a focus on TP53.

Methods: We examined high-depth NGS data from blood cell-derived DNA for mutations with pathogenic potential suggestive of mosaicism (5-30% allele frequency) in known hereditary cancer genes. For each gene, we determined the average ages of patients tested and compared these distributions to the distribution of ages of patients found to have mosaic mutations. For the mosaic TP53 mutations, we further characterized the mutations found as well as described the clinical scenarios in which the mosaic findings occurred.

Results: To date, 101 patients were found to have possibly mosaic mutations with pathogenic potential, including 26 cases with TP53 mutations (0.07% of patients tested), 16 with CHEK2 mutations (0.05%), and 16 with ATM mutations (0.05%). Significant bias towards older ages is seen in patients with ATM (p= 0.0026) and CHEK2 (p=4.2x10-6) mosaic findings. Mosaic TP53 and NF1 mutations were also enriched in older patients , although not as significantly as CHEK2 and ATM mosaic patients. 24/25 patients with TP53 mosaic mutations with a known history were cancer affected. In the COSMIC database, 20/20 of the TP53 mosaic mutations are associated with neoplastic conditions and 13/20 are associated with hematolymphoid neoplasms. 15/20 of the pathogenic mosaic TP53 findings were seen previously in our lab at a ratio corresponding to germline, thereby significantly lessening the possibility of technical artifact.

Conclusion: The statistically significant older ages of patients with ATM and CHEK2 mosaic variants suggests that many of these are acquired changes in hematopoietic stem cells rather than constitutional mosaicism per se. Although NF1 is known to be associated with constitutional mosaicism, the bias towards older patients of the NF1 mosaics we saw similarly suggests that most are acquired changes in the hematopoietic stem cells. The less significant age bias in the TP53 events suggests that chemotherapy administration may be leading to enrichment of TP53 mutated clones, although an increased rate of constitutional mosaicism cannot be ruled out.

Citation Format: Deucher A, Lincoln S, Sorenson J. Clinical significance of TP53 mosaic mutations uncovered in constitutional genetic testing [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-02-02.