16. An evaluation of clinical significance of the TP53 polyadenylation signal-disrupting variant rs78378222-G

TP53 germline pathogenic variants (Li-Fraumeni syndrome) and somatic mutations are important in tumorigenesis and tumor classifications. However, the clinical significance of the TP53 polyadenylation signal-disrupting variant rs78378222-G remains unclear. To address this, we employed a dual approach.

First, we used All of Us Research Program data to evaluate its disease association with phenome-wide association studies (PheWAS). In the trans-ancestry PheWAS (n = 245,378, 3383 were heterozygous and <20 were homozygous), the G-allele was significantly associated with uterine leiomyoma (OR = 1.75 [1.42-2.16]). In Blacks (n = 56,911, allele frequency [AF] = 0.00171), it was significantly associated with anal and rectal polyps (11.97 [4.46-32.07]), and nominally associated with hyperparathyroidism, head and neck cancer, and primary cardiomyopathies. In Whites (n = 133,572, AF = 0.0112), it was significantly associated with benign neoplasm of the uterus (1.61 [1.27-2.03]) and in Hispanics (n = 45,032, AF = 0.00276), with uterine leiomyoma (3.82 [2.11-6.84]).

Next, we imputed rs78378222 with microarray data from the Cancer Genomic Atlas (TCGA, overall carrier rate 1.9%). Adult glioma (GBMLGG) had the highest carrier rate for the G-allele (4.6% in IDH-wildtype and 3.2% in IDH-mutant). There was no evidence of differential prognosis or rates of TP53 mutation/17p loss among carriers within the evaluated tumor types that had enough carriers for analysis.

Our preliminary analyses demonstrate that TP53 rs78378222-G allele was consistently associated with higher risk of neoplasms and tissue overgrowth in multiple ancestry groups. However, its role in cancer classification and prognostication may be limited, necessitating further validation with more data.