bims-tumhet 2021-09-26 papers

Issue of 2021–09–26
four papers selected by
Sergio Marchini, Humanitas Research

Nat Commun. 2021 Sep 22. 12(1): 5574

A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer.

Panagiotis A Konstantinopoulos, Alexandre André B A da Costa, Doga Gulhan, Elizabeth K Lee, Su-Chun Cheng, Andrea E Wahner Hendrickson, Bose Kochupurakkal, David L Kolin, Elise C Kohn, Joyce F Liu, Elizabeth H Stover, Jennifer Curtis, Nabihah Tayob, Madeline Polak, Dipanjan Chowdhury, Ursula A Matulonis, Anniina Färkkilä, Alan D D'Andrea, Geoffrey I Shapiro.

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.

DOI: https://doi.org/10.1038/s41467-021-25904-w

Cell Mol Biol Lett. 2021 Sep 23. 26(1): 41

CircRNAs as potent biomarkers in ovarian cancer: a systematic scoping review.

Zahra Foruzandeh, Fatemeh Zeinali-Sehrig, Kazem Nejati, Dara Rahmanpour, Fariba Pashazadeh, Farhad Seif, Mohammad Reza Alivand.

More powerful prognostic and diagnostic tools are urgently needed for identifying and treating ovarian cancer (OC), which is the most fatal malignancy in women in developed countries. Circular RNAs (circRNAs) are conservative and stable looped molecules that can regulate gene expression by competing with other endogenous microRNA sponges. This discovery provided new insight into novel methods for regulating genes that are involved in many disorders and cancers. This review focuses on the dysregulated expression of circRNAs as well as their diagnostic and prognostic values in OC. We found that studies have identified twenty-one downregulated circRNAs and fifty-seven upregulated ones. The results of these studies confirm that circRNAs might be potent biomarkers with diagnostic, prognostic and therapeutic target value for OC. We also consider the connection between circRNAs and OC cell proliferation, apoptosis, metastasis, and chemotherapy resistance and sensitivity.

Keywords: Circular RNA (CircRNA); Ovarian cancer (OC)

DOI: https://doi.org/10.1186/s11658-021-00284-7

Gynecol Oncol Rep. 2021 Nov;38 100847

Liquid biopsy with droplet digital PCR targeted to specific mutations in plasma cell-free tumor DNA can detect ovarian cancer recurrence earlier than CA125.

Takamichi Minato, Shin Ito, Bin Li, Haruna Fujimori, Mai Mochizuki, Kazunori Yamaguchi, Keiichi Tamai, Muneaki Shimada, Hideki Tokunaga, Shogo Shigeta, Ikuro Sato, Hiroshi Shima, Hidekazu Yamada, Nobuo Yaegashi, Jun Yasuda.

Objective: Ovarian cancer (OC) is an intractable gynecological tumor, and frequent recurrence is experienced within a few years even after the complete eradication of tumor tissues by radical resection and neo-adjuvant chemotherapies. The conventional recurrence marker, CA125, is widely used for follow-up after resection of OC, but CA125 has a long half-life in blood and lacks dynamic responses to tumor recurrence. Recent developments in liquid biopsy procedures are expected to overcome the difficulties in early diagnosis of OC recurrence after surgery.
Methods: We applied droplet digital PCR (ddPCR) technology to detect circulating tumor-derived DNA in OC patients' plasma during follow-up. Exome sequencing of 11 tumor-normal pairs of genomic DNA from consecutive OC patients identified tumor-specific mutations, and ddPCR probes were selected for each sample.
Results: Six of 11 cases showed apparent recurrence during follow-up (mean progression-free survival was 348.3 days) and all six cases were positive in ddPCR analyses. In addition, ddPCR became positive before increased plasma CA125 in five out of six cases. Increased allele frequency of circulating tumor DNA (ctDNA) is associated with increased tumor volume after recurrence. ddPCR detected ctDNA signals significantly earlier than increased CA125 in the detection of OC recurrence by imaging (49 days and 7 days before, respectively: p < 0.05). No ctDNA was detected in the plasma of recurrence-free cases.
Conclusions: Our results demonstrate the potential of identifying ctDNA by ddPCR as an early detection tool for OC recurrence.

Keywords: CA125; Ovarian cancer; ctDNA; ddPCR

DOI: https://doi.org/10.1016/j.gore.2021.100847

Cell Rep. 2021 Sep 21. pii: S2211-1247(21)01171-2. [Epub ahead of print]36(12): 109722

DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity.

DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation.

Keywords: 3D genome organization; DNA methylation; allele-specific replication; cancer; chromatin; epigenome; replication timing; single-cell sequencing

DOI: https://doi.org/10.1016/j.celrep.2021.109722