br Fig Mutational signature associated
Fig. 3. Mutational signature 3 associated with homologous recombination DNA repair defects in copy-number high (serous-like) endometrial cancers, high-grade serous ovarian cancers and basal-like breast cancers from The Cancer Genome Atlas. Mutational signatures were defined for copy-number high (serous-like) endometrial cancers (n = 60), high-grade serous ovarian cancers (n = 225) and basal-like breast cancers (n = 146) with ≥20 single nucleotide variants from The Cancer Genome Atlas (TCGA) [3,15,16], color-coded according to the legend. Cases are sorted by the proportion of signatures 3 and 1. The percentage of each 444890-41-9 signature and the total number of non-synonymous somatic mutations for each case are shown below. HRD, homologous recombination DNA repair deficiency; MSI, microsatellite instability.
Fig. 4. Mutational signatures of uterine carcinosarcomas. Mutational signatures for 57 primary treatment-naïve uterine carcinosarcomas from The Cancer Genome Atlas (TCGA) , sorted by the proportion of signature 1, and color-coded according to the legend. The number of non-synonymous somatic mutations per case, age at diagnosis, stage, histologic subtype, histologic classification, percentage of carcinoma in the frozen tissue subjected to whole-exome sequencing, percentage of sarcoma in the frozen tissue subjected to whole-exome sequencing, MSIsensor score, MLH1 promoter methylation and POLE mutations are provided below the signatures. HRD, homologous recombination DNA repair deficiency; MSI, microsatellite instability; NOS, not otherwise specified.
Finally, the shared mutations of EC22 displayed a dominant signa-ture 6, as well as APOBEC signatures 2 and 13 and the HRD-related sig-nature 3. Whilst a shift in the mutational signatures was observed and the primary tumor mutations displayed a dominant APOBEC-related signature 13, the mutations private in the metastasis had a dominant HRD-related signature 3. Both the primary tumor and its metastasis har-bored a p.R15W germline mutation affecting UIMC1, which encodes the BRCA1-interacting protein RAP80 and plays a role in BRCA1-mediated DNA damage responses by recruiting BRCA1 to DNA double-strand breaks . Importantly, bi-allelic inactivation of UIMC1, through LOH of the wild-type allele, was only detected in the metastasis. Consistent with this finding, we found that the LST score was only high in the me-tastasis of EC22 (LST score 20), but not in the primary tumor (LST score 14), providing evidence to suggest that defective HR, likely driven by UIMC1 bi-allelic inactivation, may have contributed to the progression to metastatic disease in this EC.
Taken together, the acquisition of additional genetic instability, through defects in DNA repair mechanisms including DNA MMR, APOBEC and HR, may play a role in the progression from primary EC to metastatic disease and may have therapeutic implications.
Here we demonstrate that the genomes of endometrioid ECs of POLE (ultramutated) and MSI (hypermutated) molecular subtypes are shaped by specific mutational processes (i.e. loss of polymerase proof-reading and MSI), whilst in endometrioid and serous ECs of copy-number low/high subtypes and uterine carcinosarcomas aging-related mutational processes are the most dominant. The mutational signature
analysis performed here expands on the TCGA molecular classification, demonstrating that there is heterogeneity in the mutational processes even among tumors of the same molecular subtype. In fact, MSI-high tu-mors were found to lack a dominant MSI mutational signature in 15% of cases and only 15% of copy-number high (serous-like) cancers had an HRD signature. In addition, we have observed that whilst the TCGA molecular subtype of an EC is generally stable from primary tumor to metastasis, mutational signature shifts from primary to metastatic en-dometrial cancer take place in N25% of ECs, suggesting that additional defects in DNA repair mechanisms may drive or be acquired in the pro-gression of ECs. These findings support the notion that the biological processes that drive the development of ECs may differ from those that result in their progression. Furthermore, these results impact on the delivery of precision medicine approaches for EC patients, given that mutational signatures and a clear understanding of the underlying mutagenic processes/pathways present in a given cancer may inform treatment options, in particular in the absence of a targetable mutation or gene copy number alteration (e.g. genomic features of HRD even in the absence of bi-allelic BRCA1/BRCA2 inactivation). Importantly, given the shifts observed in the mutational signatures between the primary tumor and metastasis in a subset of cases, one could speculate that in the advanced setting, genomics analyses should be performed on the metastasis rather than the primary tumor.