Integrative pathway analysis of gynecological tumors characterized by different chromosomal instability patterns

Gynecological tumors include four tumor types from TCGA: ovarian cancer (OV), cervical cancer (CESC), endometrial cancer (UCEC) and the rare uterine carcinosarcoma (UCS). Breast cancer (BRCA) can also be included among gynecological tumors, since it shares the same embryonic origin and the influence of female hormones. In order to shed light on the common molecular features characterizing the five tumors, molecular profiles from patients with different patterns of chromosomal instability (CIN), underlying different mechanisms of dysregulation (signatures), were compared at both expression and methylation level. A pathway analysis was performed using SourceSet software, whose topological approach allows to discriminate genes that are the primary source of dysregulation from those that are indirectly affected. Two signatures were investigated: CX1 and CX3. CX1 is characterized by defective mitotic spindle checkpoint, resulting in incorrect chromosome segregation, while CX3 shows replication stress, leading to double strand breaks that are not properly corrected by homologous recombination and result in structural aberrations. Results revealed that OV, UCEC and BRCA tend to have similar expression and methylation profiles, while UCS and CESC are the most divergent tumors. Primary genes are more uniformly detected across tumor types compared to secondary genes, reflecting the common origin of perturbation generating the observed pattern of CIN and the different molecular profiles characterizing different tissues, respectively.