**4. Ovarian cancer risk factors**

#### **4.1. Hereditary and genetic risk factors**

Ovarian cancer risk is causally linked to both lifestyle and genetics. Firstly, hereditary ovarian cancer accounts for approximately 5–15% of all cases [197] and are often diagnosed at an earlier age than sporadic disease. Furthermore, hereditary ovarian cancer tends to be of the high-grade serous subtype [198]. Therefore, patients with a first or second-degree relative with ovarian cancer have an increased risk of developing the disease (**Figure 9**). Specifically, there is a 2.5% risk of ovarian cancer in woman who report a sister EOC and a 9% risk if their mother has been previously diagnosed [197]. Familial ovarian cancer was first observed in Lynch syndrome (a disease associated with familial cancer due to inherited mutations in DNA repair machinery) in the 1970s [199, 200]. Multiple group and genomic mapping studies of breast and/ or ovarian cancer-prone families ultimately led to the identification of inherited mutations in *BRCA1* [201] and later *BRCA2* [202, 203]. The prevalence of *BRCA1* or *BRCA2* mutations in the populations has been estimated from 0.1–0.3%, and 0.1–0.7%, respectively, in Caucasians with European origins [204–206]. *BRCA1* and *BRCA2* are mutated in the germline of approximately 9–13% patients with hereditary ovarian cancer [207–209]. For mutations in *BRCA1,* the estimated average risk of ovarian cancers ranges from 20 to 50% [210–214]. For *BRCA2,* average risk estimates range from 5 to 23% [210–214]. Mutation-specific cancer risks have been reported that suggest ovarian cancer cluster region (OCCR) exist in both *BRCA1* and *BRCA2* [211, 215]. The prevalence and spectrum of mutations in *BRCA1* and *BRCA2* have been reported in single populations with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of *BRCA1* or *BRCA2 (*CIMBA) has assembled data on more than 26,000 *BRCA1* and nearly 17,000 *BRCA2* female mutation carriers from 69 centers in 49 countries on six continents [216–222]. Ongoing studies by Tim Rebbeck and the CIMBA consortium have comprehensively evaluated the characteristics of the over 1600 unique *BRCA1* and more than 1700 unique *BRCA2* deleterious (disease-associated) mutations found in the carriers [215]. The most common mutation types in these genes are frameshift mutations, followed by nonsense mutations. Therefore, understanding the type of mutations in *BRCA1* or *BRCA2* is important for risk assessment and determining medical management for patients. Most subtypes of ovarian cancer have been linked to *BRCA1* or *BRCA2* germline mutations but the development of HGS disease is the most common in these women carriers [223]. *BRCA1* and *BRCA2* mutations are more common in Ashkenazi Jewish women [206, 224, 225] due to the three common Jewish founder mutations *BRCA1* c.5266dup (5382insC) and *BRCA1* c.68\_69del (185delAG) and *BRCA2* c.5946del (6174delT) which have long been used as a primary genetic screening test for women of Jewish descent. Other mutations that are relatively common in specific populations, referred to as founder mutations, can be used to in limited screening tests. For example, in Iceland, only two mutations have been reported: the common founder mutation *BRCA2* c.771\_775del and the rarer *BRCA1* c.5074G > A [226]. Despite having a higher risk for developing ovarian cancer, *BRCA1/2* carriers have a better clinical outcome in terms of survival, with *BRCA2* carriers having a more favorable outcome than *BRCA1* carriers [54]. This

the ovarian surface the fallopian tube that helps repair the damage to the ovarian surface following follicle release [192]. Notch and Wnt, canonical stem cell pathways, have been shown to regulate differentiation in fallopian tube organoids and could contribute to fallopian tube

tube and are capable of clonal growth and self-renewal [194, 195]. Since these stem cell niches are located near the areas of ovarian and fallopian surface repair and precursor lesions they could be hotspots for the development of tumors from mutations in somatic stem cells. One recent study has shown that *SOX2* is overexpressed in the fallopian tubes of patients with HGS disease and in *BRCA1*/*BRCA2* mutation carries [196], indicating a possible stem cell precursor lesion. The role of stem cells in cancer and cancer progression will remain an influential area of research and can provide potential insight into ovarian cancer pathogenesis in the future.

Taken together, these data support that the pathogenesis of ovarian cancer is complex and thus contributes to the clinical difficulties in detecting the disease early. As our understanding of the genomic complexities of ovarian cancer continues to evolve and the cell type of origin is further defined, we should be able to use this information to improve detection at a time when disease can be cured and develop more precise therapies based on tumor profiling and

Ovarian cancer risk is causally linked to both lifestyle and genetics. Firstly, hereditary ovarian cancer accounts for approximately 5–15% of all cases [197] and are often diagnosed at an earlier age than sporadic disease. Furthermore, hereditary ovarian cancer tends to be of the high-grade serous subtype [198]. Therefore, patients with a first or second-degree relative with ovarian cancer have an increased risk of developing the disease (**Figure 9**). Specifically, there is a 2.5% risk of ovarian cancer in woman who report a sister EOC and a 9% risk if their mother has been previously diagnosed [197]. Familial ovarian cancer was first observed in Lynch syndrome (a disease associated with familial cancer due to inherited mutations in DNA repair machinery) in the 1970s [199, 200]. Multiple group and genomic mapping studies of breast and/ or ovarian cancer-prone families ultimately led to the identification of inherited mutations in *BRCA1* [201] and later *BRCA2* [202, 203]. The prevalence of *BRCA1* or *BRCA2* mutations in the populations has been estimated from 0.1–0.3%, and 0.1–0.7%, respectively, in Caucasians with European origins [204–206]. *BRCA1* and *BRCA2* are mutated in the germline of approximately 9–13% patients with hereditary ovarian cancer [207–209]. For mutations in *BRCA1,* the estimated average risk of ovarian cancers ranges from 20 to 50% [210–214]. For *BRCA2,* average risk estimates range from 5 to 23% [210–214]. Mutation-specific cancer risks have been reported that suggest ovarian cancer cluster region (OCCR) exist in both *BRCA1* and *BRCA2* [211, 215]. The prevalence and spectrum of mutations in *BRCA1* and *BRCA2* have been reported in single populations with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of *BRCA1* or *BRCA2 (*CIMBA) has assembled data on more than 26,000 *BRCA1* and nearly 17,000 *BRCA2* female mutation carriers from 69 centers in 49 countries on six continents [216–222]. Ongoing studies by Tim Rebbeck and the

and PAX8+

) can be isolated from distal end of the

repair [193]. Fallopian stem-like cells (CD44<sup>+</sup>

16 Ovarian Cancer - From Pathogenesis to Treatment

precision medicine.

**4. Ovarian cancer risk factors**

**4.1. Hereditary and genetic risk factors**

**Figure 9.** Hereditary ovarian cancer and BRCA mutations. Pedigree descripting "BRCAness" and risk of ovarian cancer (top). The relative risk and prognosis for women with germline *BRCA1/2* mutations.

phenomenon is thought to be due to *BRCA2* carriers responding better to platinum-based chemotherapy [227]. However, the survival benefit decreases when examined over 10 years in HGS instead of 5 years [228]. Over time, this could be possible due to secondary intragenic mutations in *BRCA1* and *BRCA2* that restore the wild-type reading frame (conversion back to a functional BRCA) and losing favorable responses to chemotherapy [229].

age of 60 and the disease being extremely rare in patients under 40 years of age [243]. As previously discussed, surgical procedures such as tubal ligation, salpingectomy and unilateral or bilateral oophorectomy have varying degrees of success for the development of ovarian cancer by removal of the organs from which the cancer develops [244, 245]. In women with a *BRCA1* or *BRCA2* mutation, risk-reducing salpingo-oophorectomy (RRSO) decreased the lifetime risk of developing ovarian and breast cancer [165]. In a multicenter study, RRSO was associated with an 85% reduction in *BRCA1*-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56), while protection against *BRCA2*-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, its effect did not reached statistical significance [246]. The effects of RRSO can influence risk for each subtype given the nature of development from different tissues, hence why bilateral oophorectomy has a stronger influence on the development of HGS disease, since it is believed to develop from the fallopian tubes. Lifestyle factors which influence complete cycling during menstruation have some of the strongest effects on the risk of developing ovarian cancer. This hypothesis is attributed to incessant ovulation, in which the release of eggs from the ovary, the fusion on the fallopian tube and the rebuilding of the uterine wall all contribute to pathogenesis of ovarian cancer [141, 148]. One of the most common factors which can alter complete cycling is the use of oral contraceptives [243]. The increase in use of oral contraceptives could be attributed to the decrease in ovarian cancer in the last decade. The longer use of oral contraceptives has been shown to correlate to lower risk of developing ovarian cancer [247, 248]. The risk is reduced in both *BRCA* wild-type and mutant carriers [249] [250]. The risk of developing each subtype is decreased following oral contraceptive use, with the exception of clear cell carcinoma [251]. However, the associated side effects make it a poor treatment for prevention alone [252]. Another factor that can influence menstrual cycles and the risk of ovarian cancer is child birth [253], in specific the age at first birth and the number of births. In fact, it was discovered the risk of ovarian cancer decreases by approximately 10% for each 5-year increment in age at first birth [254]. Also, the number of births for a given women has additive decrease in the risk of ovarian cancer, decreasing by about 8% for each birth [255], while the age of each woman at the onset of menopause had a weak association [129, 256].

Ovarian Cancer Genetics: Subtypes and Risk Factors http://dx.doi.org/10.5772/intechopen.72705 19

Other lifestyle factors can influence the risk of ovarian cancer, such as hormone replacement therapy, breast feeding, obesity and inflammation. Hormone replacement therapy increases the risk of developing ovarian cancer, depending on the therapy. For instance, the use of estrogen increases the risk of developing ovarian cancer by 22%, while the combination of estrogen and progesterone only has about a 10% chance of developing ovarian cancer [257–259]. A meta-analysis showed a similar risk for developing both HGS and endometrioid ovarian cancer in menopausal women [260]. Conversely, hormone replacement given for menopause symptoms may improve survival of ovarian cancer patients [261]. Another reproductive factor is breastfeeding, in *BRCA1* mutant carriers breastfeeding lead to a reduced the risk of developing ovarian cancer [129, 243]. Meta-analysis also suggests the duration of lifetime breastfeeding is additive in reducing the risk of developing ovarian cancer [262]. Like many other cancers, cigarette smoking and alcohol consumption have at least some association with increasing the risk of developing ovarian cancer. Specifically, smoking is associated with an increased risk of developing clear cell and endometrial ovarian cancer but not serous [263]. Smoking increased the risk of mucinous ovarian cancer, but cessation returns can reduce the

As indicated, the location of the alteration within *BRCA1* or *BRCA2* may vary the risk of breast and ovarian cancer [215], but other studies including genome-wide association study (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with risk of ovarian cancer for women in the general population [230]. Four of these SNP, *i.e.,* rs10088218, rs2665390, rs717852, rs9303542, were associated with ovarian cancer risk in *BRCA2* carriers, while two loci (rs10088218 and rs2665390) were associated with ovarian cancer risk in *BRCA1* carriers [217]. Inherited variants in other loci along with *BRCA1* or *BRCA2* mutations can better predict the risk of either breast or ovarian cancer [220], indicating the need to better understand concurrent sequence variants in women with deleterious *BRCA1* or *BRCA2* mutations. Concurrent mutations in 1p36 (*WNT4*), 4q26 (*SYNPO2*), 9q34.2 (*ABO*), and 17q11.2 (*ATAD5*) increased risk of all EOC subtypes while 1q34.3 (*RSPO1*) and 6p22.1 (*GPX6*) mutations increased the risk of serous ovarian cancer in *BRCA* carriers [231]. *BRCA1* mutation carries can have reduced risk with concurrent sequence variants in *CASP8, i.e.,* the D302H polymorphism [232]. Other genetic markers of risk, such as a variant allele of *KRAS* at *rs61764370*, referred to as the *KRAS*-variant, which disrupts a *let-7* miRNA binding site in this oncogene, is associated with sporadic and familial ovarian cancer without *BRCA1/2* mutations [233]. *PALB2*, encoding for a BRCA2 interacting protein, has increased promoter hypermethylation which results in decreased *BRCA2* function and increased risk of ovarian cancer [234]. Recent data have shown that copy number variation in *BRCA1* or *BRCA2* mutation carriers can either increase the risk (*OR2A*) or decrease the risk (*CYP2A7*) of ovarian cancer [235]. A better understanding of secondary genetic alteration in *BRCA1/2* mutant carriers can help determine the best clinical approach for managing the risk of disease.

Genetic risk factors outside of *BRCA1* or *BRCA2* mutations are not as well defined but often take place in genes involved in genomic integrity, most commonly DNA mismatch repair (MMR). SNPs in the *TERT* locus (rs2242652 and rs10069690) were associated with decreased telomere length and increased breast and ovarian cancer risk in *BRCA* mutation carriers [236]. A study that sequenced 12 genes for germline mutations in patients with ovarian cancer found *BARD1*, *BRIP1*, *CHECK2*, *MREA11*, *MSH6*, *NMN*, *PALB2*, *RAD51C*, or *TP53* were mutated in 24% of the 360 patients enrolled [237]. Genes within the Fanconi anemia pathway are also associated with developing ovarian cancer, including *RAD51C*, *RAD51D*, and *BRIP1* [238, 239]. Other MMR genes have been associated with Lynch syndrome and ovarian cancer risk *MLH1*, *PMS2*, *MSH2*, and *MSH6* [240–242].

#### **4.2. Lifestyle risk factors**

Environment and lifestyle also play a risk for developing both hereditary and sporadic ovarian cancer by either increasing or decreasing the lifetime risk of developing ovarian cancer. Like many cancers, age is a risk factor for ovarian cancer with most cases being diagnosed after the age of 60 and the disease being extremely rare in patients under 40 years of age [243]. As previously discussed, surgical procedures such as tubal ligation, salpingectomy and unilateral or bilateral oophorectomy have varying degrees of success for the development of ovarian cancer by removal of the organs from which the cancer develops [244, 245]. In women with a *BRCA1* or *BRCA2* mutation, risk-reducing salpingo-oophorectomy (RRSO) decreased the lifetime risk of developing ovarian and breast cancer [165]. In a multicenter study, RRSO was associated with an 85% reduction in *BRCA1*-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56), while protection against *BRCA2*-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, its effect did not reached statistical significance [246]. The effects of RRSO can influence risk for each subtype given the nature of development from different tissues, hence why bilateral oophorectomy has a stronger influence on the development of HGS disease, since it is believed to develop from the fallopian tubes. Lifestyle factors which influence complete cycling during menstruation have some of the strongest effects on the risk of developing ovarian cancer. This hypothesis is attributed to incessant ovulation, in which the release of eggs from the ovary, the fusion on the fallopian tube and the rebuilding of the uterine wall all contribute to pathogenesis of ovarian cancer [141, 148]. One of the most common factors which can alter complete cycling is the use of oral contraceptives [243]. The increase in use of oral contraceptives could be attributed to the decrease in ovarian cancer in the last decade. The longer use of oral contraceptives has been shown to correlate to lower risk of developing ovarian cancer [247, 248]. The risk is reduced in both *BRCA* wild-type and mutant carriers [249] [250]. The risk of developing each subtype is decreased following oral contraceptive use, with the exception of clear cell carcinoma [251]. However, the associated side effects make it a poor treatment for prevention alone [252]. Another factor that can influence menstrual cycles and the risk of ovarian cancer is child birth [253], in specific the age at first birth and the number of births. In fact, it was discovered the risk of ovarian cancer decreases by approximately 10% for each 5-year increment in age at first birth [254]. Also, the number of births for a given women has additive decrease in the risk of ovarian cancer, decreasing by about 8% for each birth [255], while the age of each woman at the onset of menopause had a weak association [129, 256].

phenomenon is thought to be due to *BRCA2* carriers responding better to platinum-based chemotherapy [227]. However, the survival benefit decreases when examined over 10 years in HGS instead of 5 years [228]. Over time, this could be possible due to secondary intragenic mutations in *BRCA1* and *BRCA2* that restore the wild-type reading frame (conversion back to a functional

As indicated, the location of the alteration within *BRCA1* or *BRCA2* may vary the risk of breast and ovarian cancer [215], but other studies including genome-wide association study (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with risk of ovarian cancer for women in the general population [230]. Four of these SNP, *i.e.,* rs10088218, rs2665390, rs717852, rs9303542, were associated with ovarian cancer risk in *BRCA2* carriers, while two loci (rs10088218 and rs2665390) were associated with ovarian cancer risk in *BRCA1* carriers [217]. Inherited variants in other loci along with *BRCA1* or *BRCA2* mutations can better predict the risk of either breast or ovarian cancer [220], indicating the need to better understand concurrent sequence variants in women with deleterious *BRCA1* or *BRCA2* mutations. Concurrent mutations in 1p36 (*WNT4*), 4q26 (*SYNPO2*), 9q34.2 (*ABO*), and 17q11.2 (*ATAD5*) increased risk of all EOC subtypes while 1q34.3 (*RSPO1*) and 6p22.1 (*GPX6*) mutations increased the risk of serous ovarian cancer in *BRCA* carriers [231]. *BRCA1* mutation carries can have reduced risk with concurrent sequence variants in *CASP8, i.e.,* the D302H polymorphism [232]. Other genetic markers of risk, such as a variant allele of *KRAS* at *rs61764370*, referred to as the *KRAS*-variant, which disrupts a *let-7* miRNA binding site in this oncogene, is associated with sporadic and familial ovarian cancer without *BRCA1/2* mutations [233]. *PALB2*, encoding for a BRCA2 interacting protein, has increased promoter hypermethylation which results in decreased *BRCA2* function and increased risk of ovarian cancer [234]. Recent data have shown that copy number variation in *BRCA1* or *BRCA2* mutation carriers can either increase the risk (*OR2A*) or decrease the risk (*CYP2A7*) of ovarian cancer [235]. A better understanding of secondary genetic alteration in *BRCA1/2* mutant carriers can help determine the

Genetic risk factors outside of *BRCA1* or *BRCA2* mutations are not as well defined but often take place in genes involved in genomic integrity, most commonly DNA mismatch repair (MMR). SNPs in the *TERT* locus (rs2242652 and rs10069690) were associated with decreased telomere length and increased breast and ovarian cancer risk in *BRCA* mutation carriers [236]. A study that sequenced 12 genes for germline mutations in patients with ovarian cancer found *BARD1*, *BRIP1*, *CHECK2*, *MREA11*, *MSH6*, *NMN*, *PALB2*, *RAD51C*, or *TP53* were mutated in 24% of the 360 patients enrolled [237]. Genes within the Fanconi anemia pathway are also associated with developing ovarian cancer, including *RAD51C*, *RAD51D*, and *BRIP1* [238, 239]. Other MMR genes have been associated with Lynch syndrome and ovarian cancer

Environment and lifestyle also play a risk for developing both hereditary and sporadic ovarian cancer by either increasing or decreasing the lifetime risk of developing ovarian cancer. Like many cancers, age is a risk factor for ovarian cancer with most cases being diagnosed after the

BRCA) and losing favorable responses to chemotherapy [229].

18 Ovarian Cancer - From Pathogenesis to Treatment

best clinical approach for managing the risk of disease.

risk *MLH1*, *PMS2*, *MSH2*, and *MSH6* [240–242].

**4.2. Lifestyle risk factors**

Other lifestyle factors can influence the risk of ovarian cancer, such as hormone replacement therapy, breast feeding, obesity and inflammation. Hormone replacement therapy increases the risk of developing ovarian cancer, depending on the therapy. For instance, the use of estrogen increases the risk of developing ovarian cancer by 22%, while the combination of estrogen and progesterone only has about a 10% chance of developing ovarian cancer [257–259]. A meta-analysis showed a similar risk for developing both HGS and endometrioid ovarian cancer in menopausal women [260]. Conversely, hormone replacement given for menopause symptoms may improve survival of ovarian cancer patients [261]. Another reproductive factor is breastfeeding, in *BRCA1* mutant carriers breastfeeding lead to a reduced the risk of developing ovarian cancer [129, 243]. Meta-analysis also suggests the duration of lifetime breastfeeding is additive in reducing the risk of developing ovarian cancer [262]. Like many other cancers, cigarette smoking and alcohol consumption have at least some association with increasing the risk of developing ovarian cancer. Specifically, smoking is associated with an increased risk of developing clear cell and endometrial ovarian cancer but not serous [263]. Smoking increased the risk of mucinous ovarian cancer, but cessation returns can reduce the risk over time [264] while heavy smoking (>10 packs per day) more than doubles the risk of developing ovarian cancer [265]. Alcohol consumption increased the risk of ovarian cancer, but seems to have an effect only in heavy drinkers. Consumption of more than 20 drinks per week is associated with increased risk [266] while with moderate use the risk is less pronounced or significant [267, 268]. Obesity is associated with less common subtypes of ovarian cancer and not HGS [269] and the lifetime risk decreases with recreation physical activity [270]. Finally, inflammation increases the risk of developing ovarian cancer [271] while the use of aspirin was shown to reduce risk of developing ovarian cancer from between 20 and 34% [272]. The use of other non-steroidal anti-inflammatory drugs (NSAIDs) showed a reduction in risk but was not significant.

**Author details**

Kansas City, KS, USA

\*, Jennifer Crow1

\*Address all correspondence to: jhirst@kumc.edu

and Andrew Godwin1,2

1 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center,

Ovarian Cancer Genetics: Subtypes and Risk Factors http://dx.doi.org/10.5772/intechopen.72705 21

2 University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS,

[1] Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: The size of the problem. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2006;**20**(2):

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[3] Seidman JD et al. The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. International Journal of Gynecological Pathology. 2004;**23**(1):41-44

[4] Gershenson DM. The heterogeneity of epithelial ovarian cancer: Getting it right. Cancer.

[5] Malpica A et al. Grading ovarian serous carcinoma using a two-tier system. The

[6] Iwabuchi H et al. Genetic analysis of benign, low-grade, and high-grade ovarian tumors.

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[10] Taylor J, McCluggage WG. Ovarian seromucinous carcinoma: Report of a series of a newly categorized and uncommon neoplasm. The American Journal of Surgical Pathology.

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Jeff Hirst<sup>1</sup>

USA

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#### **5. Conclusion**

Genetically, ovarian cancer is a heterogeneous and dynamic disease that presents several clinical and research challenges. While epithelial ovarian cancer is categorized pathologically into five basic subtypes, within each subtype exist genetic diversity that limits the development of target therapies. To add to this complexity, one of the hallmarks of serous ovarian cancer is genomic instability, which is driven by frequent *TP53* mutations and deficiencies in DNA repair pathways. While this genomic alterations have led to the development of breakthrough therapies (PARP inhibitors), they also contributes to the dynamic cell growth and frequent genomic alterations and gene expression changes which contribute to the adaptation to therapy. Likewise, the pathogenesis of ovarian cancer remains a debated field with the recent insights of progression of a subset of serous ovarian cancer from fallopian tube epithelial lesions. Progression from the fallopian tube means tumors detected on the ovarian surface are already metastatic disease, leading to quick progression and limited response to therapy. Overall, while many genetic and genomic abnormalities have been identified in ovarian cancer, additional discovers are needed to (1) improve early detection of the disease (at a time when current treatment might be curative), (2) further define molecular classifiers of response to therapy, and (3) develop therapies that will be more effective across or specific to the different molecular subtypes. Other than the very common *TP53* mutation in high-grade serous ovarian cancer (96% of cases), which to date is undruggable, and the previously mentioned *BRCA* mutations (approximately 10–12% of ovarian cancers), only a small overall percentage of tumors from patients with this malignancy will be found to possess a specific causative mutation that can be effectively targeted therapeutically. Therefore, implementation of genomicbased medicine remains a challenge for the management of women with ovarian cancer.

#### **Acknowledgements**

Pathology images for each ovarian cancer subtype generously provided by Dr. Rashna Madan from the University of Kansas Medical Center and the University of Kansas Cancer Center (Kansas City, KS).
