Cancer Associated PRDM9: Implications for Linking Genomic Instability and Meiotic Recombination

Abstract

The PR domain-containing 9 or PRDM9 is a gene recognized for its fundamental role in meiosis, a process essential for forming reproductive cells. Recent findings have implicated alterations in the PRDM9, particularly its zinc finger motifs, in the onset and progression of cancer. This association is manifested through genomic instability and the misregulation of genes critical to cell growth, proliferation, and differentiation. In our comprehensive study, we harnessed advanced bioinformatic mining tools to delve deep into the intricate relationship between PRDM9F and cancer. We analyzed 136,752 breakpoints and found an undeniable association between specific PRDM9 motifs and the occurrence of double-strand breaks, a phenomenon evidenced in every cancer profile examined. Utilizing R statistical querying and the Regioner package, 55 unique sequence variations of PRDM9 were statistically correlated with cancer, from a pool of 1024 variations. A robust analysis using the Enrichr tool revealed prominent associations with various cancer types. Moreover, connections were noted with specific phenotypic conditions and molecular functions, underlining the pervasive influence of PRDM9 variations in the biological spectrum. The Reactome tool identified 25 significant pathways associated with cancer, offering insights into the mechanistic underpinnings linking PRDM9 to cancer progression. This detailed analysis not only confirms the pivotal role of PRDM9 in cancer development, but also unveils a complex network of biological processes influenced by its variations. The insights gained lay a solid foundation for future research aimed at deciphering the mechanistic pathways of PRDM9, offering prospects for targeted interventions and innovative therapeutic approaches in cancer management.

Keywords: PRDM9; breast cancer; carcinogenesis; head and neck cancer; lung adenocarcinoma; ovarian cancer; permutation analysis R; recombination; sequence motif.

Figure 1

Consensus sequence motif of all 55 unique sequence variations of the total 1024 PRDM9 sequence variations that are correlated significantly with the four types of cancers in all of the 136,752 cancer breakpoints.

Figure 2

Breakpoints and d(CCACCATCACCAC) overlap permutation test for various type of cancer of the respective flanking frame of 500-nt. The Figure 2 depicts a gray histogram representing the evaluation of the randomized region set with a fitted normal and a black bar representing the mean of the randomized evaluations. Accordingly, the green line represents the observed hits (Evobs), while the red line represents the expected hits (Evexp), and shows the limit at which the correlation between d(CCACCATCACCAC) and 4 types of cancer can be statistically or by chance associated. The p-value is equal to 0.05 when the green line coincides with the red line. The results of the test include ovarian cancer (OVC), with p-value = 0.0014 and Z-score = 37.167; lung adenocarcinoma (LUAD), with p-value = 0.001 and Z-score = 29.346; breast cancer, with p value = 0.001 and Z-score = 8.628; and head and neck cancer (HNC), with p-value = 0.001 and Z-score = 32.987.

Figure 3

Breakpoints and d(CCACCATCACCAC) overlap permutation test for various type of cancer of the respective flanking frame of 100 nt. The Figure 3 depicts a gray histogram representing the evaluation of the randomized region set with a fitted normal and a black bar representing the mean of the randomized evaluations. Accordingly, the green line represents the observed hits (Εvobs), while the red line represents the expected hits (Evexp), and shows the limit at which the correlation between d(CCACCATCACCAC) and the 4 types of cancer can be statistically or by chance associated. The p-value is equal to 0.05 when the green line coincides with the red line The results of the test include ovarian cancer (OVC), with p-value = 0.001 and Z-score = 22.39; lung adenocarcinoma (LUAD), with p-value = 0.001 and Z-score = 23.719; breast cancer, with p value = 0.001 and Z-score = 36.359; and head and neck cancer (HNC), with p-value = 0.001 and Z-score = 30.362.

Figure 4

Results of comprehensive gene set enrichment analysis, including diseases, phenotypes, molecular functions, cellular components, biological processes, and transcription factors.

Figure 5

Bar graph of enriched terms across input gene lists, colored by p-values, based on Metascape analysis.