Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular subtype and change in treatment course
Introduction
Ovarian cancer has a poor prognosis among gynecologic malignancies [1]. High-grade serous ovarian cancer (HGSOC), which is the most frequent epithelial ovarian cancer, is commonly diagnosed as an advanced cancer [2]. HGSOC is mainly treated by chemotherapy; however, most HGSOCs recur as a chemo-resistant tumor even though the first chemotherapy is usually effective and results in lethal treatment.
The Cancer Genome Atlas (TCGA) has revealed some characteristics of the cancer genome of HGSOC. One of the characteristics is homologous recombination repair deficiency (HRD) [3]. Almost half of HGSOCs have HRD due to BRCA1/2 mutation or other homologous recombination repair pathway-related gene alterations [4]. HRD is associated with sensitivity to platinum agents [5] and poly- (ADP ribose) polymerase (PARP) inhibitors [[6], [7], [8]], and quantifying the genomic loss of heterozygosity (LOH) provides the possibility of measuring HRD as a biomarker [9]. In the ARIEL2 study, the LOH score was used as a treatment biomarker for the PARP inhibitor, and it was shown that the PARP inhibitor was effective in cases with a high LOH score [10].
The TP53 mutation can be detected at a high frequency in HGSOC [3]. TP53 mutations give rise to chromosomal instability due to disruption of the control of the cell cycle and apoptosis [11]. Chromosomal instability causes subclonal evolution, which shows different genomic characteristics in tumorigenesis and tumor progression and results in high intratumor heterogeneity [12,13], which is associated with resistance to treatment and poor prognosis [[14], [15], [16]]. We have already reported that a single nucleotide polymorphism (SNP) array with formalin-fixed paraffin-embedded specimens can be used to analyze intratumor heterogeneity [17]. With this method, we can evaluate intratumor heterogeneity from various clinical specimens and apply the findings to clinical features, such as prediction of prognosis.
Although each of these main characteristics of HGSOC was investigated in several studies, no reports have examined the association between HRD and intratumor heterogeneity and how these factors changed before and after chemotherapy. In the current study, we first investigated the association between prognosis and HRD or intratumor heterogeneity with the use of TCGA data, and second, we analyzed the changes in these factors throughout treatment of HGSOC with samples from our institution.
Section snippets
Data sources
We obtained TCGA CEL-formatted SNP array data from Affymetrix Genome-Wide Human SNP Array 6.0 via the Genomic Data Commons (GDC) Data Portal (https://portal.gdc.cancer.gov) and extracted 573 HGSOC cases with matched tumor-normal data. We obtained TCGA CEL-formatted gene expression array data from the GeneChip HT Human Genome U133A data via the GDC Data Portal and extracted cases having the same samples as the SNP array data. Additionally, we obtained TCGA XML-formatted clinical data for each
Results
CI and LOH scores could be estimated in 536 and 542 samples out of 573 samples, respectively. Both CI and LOH scores could be calculated in 502 samples, so 502 samples were subjected to analysis. The background data for patients in each sample set are shown in Supplementary Table 1. The averages and standard deviations of the CI and LOH scores were 3.53 ± 1.95 and 17.90 ± 9.41, respectively (Fig. 1A and B). The correlation coefficient between the CI and LOH scores was −0.176, which indicated a
Discussion
We analyzed intratumor heterogeneity and HRD in HGSOC with SNP array data in the current study. Some methods to analyze the intratumor heterogeneity of malignant tumors, including ovarian cancer, have previously been reported, such as multi-region sequencing [28], deep sequencing [29], and single-cell sequencing [30]. We could analyze intratumor heterogeneity from a single sampling of a tumor by applying a previous method [17], which we reported in the current study. The merit of this method is
Conclusion
We have shown that both the CI and LOH in HGSOC is related to prognosis using SNP array data from a single sample. Furthermore, we have shown that the intratumor heterogeneity of chemo-resistant tumors that remained at IDS after NAC decreased compared with that of primary tumors. This study indicated that for analysis of tumors that remain after chemotherapy, investigation of the mechanism underlying the development of chemoresistance is important; thus, further studies are needed.
Declaration of competing interest
All authors declare no conflicts of interest.
Acknowledgements
This work was supported by JSPS Grant-in-Aid for Young Scientists (B) Grant Number JP17K16873.
References (40)
- et al.
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial
Lancet Oncol.
(2014) - et al.
Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study
Lancet Oncol.
(2011) - et al.
Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial
Lancet Oncol.
(2017) - et al.
The multifaceted role of chromosomal instability in cancer and its microenvironment
Cell
(2018) - et al.
Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status
Cancer Lett.
(2017) - et al.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet
(2017) - et al.
Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: a retrospective study
Ann. Oncol.
(2015) - et al.
Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer
Eur. J. Cancer
(2016) - et al.
Cancer statistics, 2019
CA A Cancer J. Clin.
(2019) - et al.
The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin
Int. J. Gynecol. Pathol.
(2004)