Abstract
Simple SummaryFunctional aneuploidy as determined by expression of the 70 genes of the CIN70 score, influences prognosis. The importance of DNA repair protein expression and activity in this context is unclear. We can show here that a high CIN70 score is associated with increased expression of 44 proteins of the known DNA repair complexes. Among these, an association with survival was only observed for 12 proteins of DNA replication and replication-associated DNA repair. This suggests that it is not the expression of individual DNA repair proteins of a DNA repair complex that causes resistance to therapy, but rather a balanced expression and coordinated activation of corresponding signaling cascades. Inhibitors to generally block the S-phase DNA damage response should therefore be used to develop therapeutic strategies in the future.Aneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score was established. We observed an association of CIN70 score and survival in 519 HNSCC patients in the TCGA dataset; the 15% patients with the lowest CIN70 score showed better survival (p = 0.11), but association was statistically non-significant. This correlated with the expression of 39 proteins of the major repair complexes. A positive association with survival was observed for MSH2, XRCC1, MRE11A, BRCA1, BRCA2, LIG1, DNA2, POLD1, MCM2, RAD54B, claspin, a negative for ERCC1, all related with replication. We hypothesized that expression of these factors leads to protection of replication through efficient repair and determines survival and resistance to therapy. Protein expression differences in HNSCC cell lines did not correlate with cellular sensitivity after treatment. Rather, it was observed that the stability of the DNA replication fork determined resistance, which was dependent on the ATR/CHK1-mediated S-phase signaling cascade. This suggests that it is not the expression of individual DNA repair proteins that causes therapy resistance, but rather a balanced expression and coordinated activation of corresponding signaling cascades.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and accounts for approximately 4–6% of all newly diagnosed tumors
Of functional aneuploidy and tumoral mRNA expression of DNA repair proteins for survival of HNSCC patients, the CIN70 score was first determined in 519 tumor samples of the the open-access Cancer Genome Atlas (TCGA) dataset ([11]; Figure 1A)
The general DNA repair damage response mediated by the ATR/ATM signaling cascade (Figure 1B), mismatch repair (MMR; Figure 1C), single-strand break repair (SSBR; Figure 1D), the two DNA repair pathways of DNA double-strand break repair, Homologous recombination (HR) (Figure 1E) and classical non-homologous end-joining (Figure 1F), interstrand cross-link repair (ICL repair; Figure 1G), and proteins with a function in stabilizing the DNA replication fork (Figure 1H) were considered
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and accounts for approximately 4–6% of all newly diagnosed tumors. This affects genes of mismatch repair (MMR), the DNA double-strand break repair pathway homologous recombination (HR), and DNA cross-link repair (ICL repair) [3] These mutations lead to alterations in protein expression, seen in HNSCC cell lines [4], and negatively impact survival [5]. Beside genomic and chromosomal instability, the CIN70 score has been established [11] This uses a signature of genes associated with functional segmental aneuploidy. Based on this signature of genes, negative prognostic impact of CIN70 score on survival was observed for several tumor entities [11]. Important questions regarding the prognostic value of the CIN70 score, along with the expression of other DNA repair genes in HNSCC, are pending
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