Genomic landscape and evolutionary trajectories of ovarian cancer precursor lesions

Abstract

The clonal relationship between ovarian high-grade serous carcinoma (HGSC) and its presumed precursor lesion, serous tubal intraepithelial carcinoma (STIC), has been reported. However, when analyzing patients with concurrent ovarian carcinoma and tubal lesion, the extensive carcinoma tissues present at diagnosis may have effaced the natural habitat of precursor clone(s), obscuring tumor clonal evolutionary history, or may have disseminated to anatomically adjacent fimbriae ends, masquerading as precursor lesions. To circumvent these limitations, we analyzed the genomic landscape of incidental tubal precursor lesions including p53 signature, dormant STIC or serous tubal intraepithelial lesion (STIL) and proliferative STIC in women without ovarian carcinoma or any cancer diagnosis using whole-exome sequencing and amplicon sequencing. In three of the four cancer-free women with multiple discrete tubal lesions we observed non-identical TP53 mutations between precursor lesions from the same individual. In one of the four women with co-existing ovarian HGSC and tubal precursor lesion we found non-identical TP53 mutations and a lack of common mutations shared between her precursor lesion and carcinoma. Analyzing the evolutionary history of multiple tubal lesions in the same four patients with concurrent ovarian carcinoma indicated distinct evolution trajectories. Collectively, the results support diverse clonal origins of tubal precursor lesions at the very early stages of tumorigenesis. Mathematical modeling based on lesion-specific proliferation rates indicated that p53 signature and dormant STIC may take a prolonged time (two decades or more) to develop into STIC, whereas STIC may progress to carcinoma in a much shorter time (6 years). The above findings may have implications for future research aimed at prevention and early detection of ovarian cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: STIC; STIL; detection; ovarian cancer; p53 signatures; prevention.

Figure 1

Locations of precursors and cancerous lesions and numbers of somatic mutations detected in these lesions. (A) Representative tissue section containing STIC before and after LCM. Arrows indicate the locations of STICs before (left) and after (right) LCM. (B) Schematic of lesion distribution in 11 patients whose lesions were analyzed by whole‐exome sequencing. Red bars, HGSCs; orange bars, proliferative (active) STICs; yellow bars, dormant STICs; green bars, p53 signatures.

Figure 2

Genome‐wide allelic imbalance analysis. (A) Genome‐wide allelic imbalance profiles. Minor allele frequencies of heterozygous SNPs identified from normal samples were calculated for each lesion sample and segmented using the circular binary segmentation algorithm. The mean minor allele frequencies of chromosomal segments are depicted as a heatmap. In cases 6, 9 and 146, different lesions from the same individual shared segments of allelic imbalance, suggesting clonal relationships between these lesions. In contrast, there are no shared subchromosomal segments of allelic imbalance among different lesions in cases 5 and 13. (B–D) Comparison in the numbers of genetic alterations per lesion among different precursors and HGSC. Data are presented as mean ± SD. P values were calculated using the Kruskal–Wallis test.

Figure 3

Genomic analysis of incidental tubal lesions in case 13 without concurrent or a history of cancer. (A) Top: the locations of six distinct lesions on Fallopian tube tissue sections. Bottom: representative photomicrographs of two lesions and their corresponding TP53 mutation status. (B) The phylogenetic tree of multiple lesions in case 13.

Figure 4

Phylogenetic trees of cases with concurrent tubal precursors and ovarian HGSC. Branch length was proportional to the number of somatic mutations and subchromosomal LOH; longer branches indicate more genomic differences. Evolutionary branching patterns reflect clonal relationships between lesions. Branches are labeled with cancer‐driver genes as well as numbers of accumulated mutations and LOH events. Circles marked with ‘G’ indicate the ancestral (germline) clone.