New Challenges in Tumor Mutation Heterogeneity in Advanced Ovarian Cancer by a Targeted Next-Generation Sequencing (NGS) Approach

Abstract

Next-generation sequencing (NGS) technology has advanced knowledge of the genomic landscape of ovarian cancer, leading to an innovative molecular classification of the disease. However, patient survival and response to platinum-based treatments are still not predictable based on the tumor genetic profile. This retrospective study characterized the repertoire of somatic mutations in advanced ovarian cancer to identify tumor genetic markers predictive of platinum chemo-resistance and prognosis. Using targeted NGS, 79 primary advanced (III-IV stage, tumor grade G2-3) ovarian cancer tumors, including 64 high-grade serous ovarian cancers (HGSOCs), were screened with a 26 cancer-genes panel. Patients, enrolled between 1995 and 2011, underwent primary debulking surgery (PDS) with optimal residual disease (RD < 1 cm) and platinum-based chemotherapy as first-line treatment. We found a heterogeneous mutational landscape in some uncommon ovarian histotypes and in HGSOC tumor samples with relevance in predicting platinum sensitivity. In particular, we identified a poor prognostic signature in patients with HGSOC harboring concurrent mutations in two driver actionable genes of the panel. The tumor heterogeneity described, sheds light on the translational potential of targeted NGS approach for the identification of subgroups of patients with distinct therapeutic vulnerabilities, that are modulated by the specific mutational profile expressed by the ovarian tumor.

Keywords: HGSOC; NGS; TP53; advanced ovarian cancer; concurrent somatic mutations; driver actionable genes; platinum sensitivity; translational medicine; tumor profile.

Figure 1

Mutational landscape in advanced ovarian tumors (n = 79) by NGS. (a) Somatic profile in HGSOCs (n = 64). (b) Somatic profile in non-HGSOCs (n = 15). (c) A bar graph represents the single-nucleotide variants (SNVs) found in advanced ovarian tumors. VAF: variant allele frequency; INDEL: insertion or deletion leading to in-frame or frameshift change; HGSOC: high-grade serous ovarian cancer; Uncl: unclassified; Endom: endometrioid; Undif: undifferentiated; Trans: transitional; Clear: clear cells; Mucin: mucinous.

Figure 2

Mutation frequencies by ovarian cancer histological subtypes (n = 79) patients with advanced ovarian cancer. Mutation frequency was calculated as the number of variant occurrences within each gene divided for the total number of patients in the following ovarian cancer histological subtypes: (a) HGSOCs; (b) Endometrioid; (c) Mixed; (d) Undifferentiated (e) Mucinous; (f) Transitional; (g) Clear cells; (h) Unclassified. HGSOC: high-grade serous ovarian cancer.

Figure 3

Number of concurrent mutations identified in driver actionable genes of the panel in seven patients with high-grade serous ovarian cancer (HGSOC).

Figure 4

TP53 mutational landscape and correlation with platinum sensitivity. (a) A bar graph represents the SNVs in TP53 found in advanced ovarian tumors (All, n = 79), including HGSOCs (HGSOC, n = 64). (b) Distribution of GOF, LOF and Uncl mutations in TP53 according to platinum sensitivity in HGSOCs. HGSOC: high-grade serous ovarian cancer. GOF: gain-of-function; LOF: loss-of-function; Uncl: unclassified. *p value < 0.05.