Ovarian cancer: Status of homologous recombination pathway as a predictor of drug response
Introduction
Ovarian cancer (OC) is the second most frequent gynecological cancer and the leading cause of death from a gynecological cancer among European women, with an estimated 42,700 deaths in 2012 (Ferlay et al., 2013). It comprises a large array of histologic, biological and genetic features, and is usually divided into three groups: epithelial malignancies which represent the most common type (90%), stromal tumors and germ cell tumors (Morgan et al., 2014). According to a recent classification based on their histology, molecular biology and natural history (Kurman and Shih Ie, 2011), epithelial ovarian carcinomas (EOC) can be further subdivided into two broad categories. Type I tumors consist of low-grade serous, endometrioid, clear cell, mucinous and transitional carcinomas. They are typically present as large masses that are confined to one ovary (stage Ia), are indolent, generally cured by surgery alone and they demonstrate low chemosensitivity. Type II tumors account for the majority of EOC (75%) and include high-grade serous ovarian carcinomas (HGSOC), undifferentiated carcinomas and carcinosarcomas. They are of high histological grade, are diagnosed at advanced stage (III/IV) and show good chemosensitivity but poor outcome.
At the molecular level, type II tumors are characterized by frequent alterations of DNA damage pathways. DNA damage repair can be divided into pathways that repair damage of one of the DNA strands (mismatches, bulky adducts, single-strand break) or damage that affects both DNA strands (crosslinks, double-strand breaks (DSBs)) (Vollebergh et al., 2012). In the presence of DSBs, repair systems no longer depend on the complementary strand for correct repair. Depending on the phase of cell cycle, DSBs are repaired either by non-homologous end joining (NHEJ) which takes place in G0-G1 phase and is error-prone or by homologous recombination (HR), which takes place in the S or G2 phase and is error-free (Vollebergh et al., 2012). HR pathway (which includes breast cancer susceptibility gene 1 (BRCA1) and BRCA2) appears to be the major mechanism for protecting the integrity of the genome in proliferating cells (Roy et al., 2012). It repairs DSBs by using the homology of the sister chromatid as a template. Fanconi anemia (FA) is a rare recessive inherited genomic instability disorder, caused by mutations in genes regulating replication-dependent removal of DNA inter-strand crosslinks (ICLs) (Moldovan and D’Andrea, 2009). FA pathway (which includes BRCA2) has functional overlap with HR pathway.
In this review, we will focus on genes that play an important role in DNA repair process (Roy et al., 2012, Pennington et al., 2014), and whose germline mutations are associated with increased risk of EOC. We will describe their involvement in HR pathway and their impact on response to DNA damaging agents, namely platinum, alkylating agents and poly(ADP-ribose) polymerase (PARP) inhibitors.
Section snippets
Molecular pathogenesis of epithelial ovarian cancer
Types I and II EOC have distinct molecular profiles reflecting different disease entities. Type I EOC are genetically stable, characterized by different mutation profiles depending on the histological subtype. For instance, low grade serous EOC show frequent somatic mutations of the MAPKinase pathway genes (KRAS and BRAF), whereas endometriosis-associated (clear cell and endometroid) carcinomas have mutations of ARID1A, CTNNB1 and PIK3CA. Finally, mucinous OC are characterized by mutations of
DNA damage and homologous recombination (HR)
One aspect of maintaining genomic integrity is mediated by a cellular network of signaling events named DNA damage response (DDR) that is triggered in response to genotoxic stress. Different DNA damage repair mechanisms exist, as resumed in Table 1 (Roco et al., 2014, Camps et al., 2007). Small base adducts are repaired by a mechanism named base excision repair (BER). Bulkier single-strand lesions that distort the DNA helical structure, such as those caused by ultraviolet, are processed by
Germline mutations of HR pathway and associated risks for epithelial ovarian cancer
The BRCA1 gene has been mapped in 1990 by Mary-Claire King’s group, (Hall et al., 1990) and subsequently cloned in 1994 (Miki et al., 1994). Shortly after, BRCA2 was characterized (Wooster et al., 1994) Germline mutations in BRCA1/BRCA2 confer increased risks of breast and ovarian cancer. A combined analysis of 22 studies involving around 8,000 patients unselected for family history found average cumulative risks in BRCA1 mutation carriers by age 70 years of 65% (95% confidence interval [CI]
Germline mutations of HR pathway and prognosis of epithelial ovarian cancer
Early after the identification of BRCA1 in 1994 (Miki et al., 1994), questions raised concerning the outcome of OC patients carrying germline mutations. The first detailed case-control study (53 BRCA1-mutated patients and 53 matched controls) reported in 1996 a substantial beneficial effect of BRCA1 germline mutations on survival of EOC patients (Rubin et al., 1996), with a median survival more than doubling, estimated to 77 months, as compared with 29 months for the matched controls (p < 0.001).
Somatic alterations of HR pathway in epithelial ovarian cancer
In the last ten years, evidences suggest that several mechanisms are involved in dysfunction of BRCA1/BRCA2 genes in EOC. Germline BRCA1 and BRCA2 truncating mutations are accompanied with somatic loss of the second intact allele resulting in loss of heterozygosity in 100% and 76% of the cases, respectively (Kanchi et al., 2014). The second intact allele can also be inactivated by mutation. Other mechanisms include somatic mutations (Hennessy et al., 2010) and promoter hypermethylation (Hilton
BRCA1/BRCA2 secondary mutations and platinum resistance
BRCA1/BRCA2-mutated cancer cells are hypersensitive to platinum agents and BRCA carriers have higher response rates to platinum-based chemotherapy compared with those with sporadic disease. However, a substantial proportion of platinum sensitive tumors became resistant at relapse (Alsop et al., 2012). One major mechanism has been identified through in vitro studies that showed how acquired resistance to cisplatin was mediated by secondary intragenic mutations in BRCA2 which restored the
Poly(ADP-ribose) polymerase (PARP) inhibitors and beyond
In the past ten years, the concept of synthetic lethality has emerged as a potential powerful tool in the treatment of cancer. According to the definition by W.G. Kaelin Jr, “two genes are synthetic lethal if mutation of either alone is compatible with viability but mutation of both leads to death” (Kaelin, 2005). The nuclear enzyme PARP-1 is a key enzyme involved in single- strand breaks (SSBs) repair by the BER pathway (Ashworth, 2008, Ame et al., 2004). In the absence of PARP activity, these
Screening tools for somatic HR defects
The concept of “BRCAness” has emerged in 2004 to describe sporadic ovarian and breast cancers that phenotypically resemble BRCA-inactivated tumors (Turner et al., 2004). It comprises all mutations leading to functional BRCA deficiency and aberrant promoter hypermethylation resulting in reduced expression of BRCA1 (BRCA2 promoter being exceptionally hypermethylated) (Cunningham et al., 2014, Turner et al., 2004, Press et al., 2008). One consequence of DNA repair impairment caused by loss of HR
Perspectives
Our rapidly expanding knowledge of genes and signaling pathways involved in DNA repair mechanisms and the recent discovery of numerous genomic alterations in the HR pathway associated with EOC is a promising step for the treatment of both BRCA-deficient and BRCA-proficient cancers. So far, these findings have allowed the development of several (functional) assays to assess the HR status that have shown encouraging results, but still need to be validated in prospective cohorts in order to find
Conflict of interest
None.
Nicolas De Picciotto (MD) is resident in medical oncology at Center of Oncology, Geneva University Hospitals (Geneva, Switzerland).
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2021, Cancer Treatment ReviewsCitation Excerpt :The last decade witnessed the rapid development of poly(ADP-ribose) polymerases (PARP) inhibitors (PARPi), a new class of oral agents first developed to induce death by synthetic lethality in deficient BRCA1/BRCA2 cancer cells [6]. Impairing response to DNA single-strand breaks with PARPi and/or DNA double-strand breaks (DSBs) with alkylating/platinum chemotherapy brought a remarkable anticancer efficacy in BRCA mutated cancer cells [8]. Hence, for HGOC patients, in addition to the backbone carboplatin-paclitaxel chemotherapy and complete debulking surgery (when possible), two classes of targeted therapies were approved in the maintenance setting in the last decade.
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Nicolas De Picciotto (MD) is resident in medical oncology at Center of Oncology, Geneva University Hospitals (Geneva, Switzerland).
Intidhar Labidi-Galy (MD, PhD) is medical oncologist at Center of Oncology, Geneva University Hospitals (Geneva, Switzerland). She is specialized in breast and ovarian cancers with a specific focus on biomarkers predictive for response to treatment.