Keywords

8.1 Introduction

The endpoint of clinical research on hereditary tumors is to reduce mortality for cancer. However, effective screening systems have not been established for detecting ovarian cancer; therefore, risk-reducing salpingo-oophorectomy (RRSO) remains the most effective ovarian cancer prevention strategy for mutation carriers. Furthermore, genetic testing for hereditary tumors is used alongside companion diagnostics to select the appropriate chemotherapy regimens, such as poly (ADP-ribose) polymerase (PARP) inhibitors for carriers of the BRCA1 and/or BRCA2 (BRCA1/2) mutations.

In this chapter, hereditary tumors, genetic testing, cancer prevention for unaffected mutation carriers, and companion diagnostics for ovarian cancer patients with BRCA1/2 mutations are described.

8.2 Carcinogenesis of Hereditary Tumors

Both genetic and environmental factors can cause cancers (Fig. 8.1). Germ-line mutations are the underlying cause of hereditary tumors, many of which are autosomal dominant diseases. If a parent harbors a mutant allele, 50% of the mutation carrier’s children are likely to be mutation carriers (Fig. 8.2). The two-hit hypothesis formulated by Alfred Knudson [1] stated that multiple hits are necessary to cause cancer (Fig. 8.3); this may explain why hereditary tumors frequently involve onset at a younger age and tend to exhibit multiple lesions and bilateral diseases more frequently (Fig. 8.4) [1].

Fig. 8.1
figure 1

Environmental and genetic factors in diseases. Many diseases, including cancer, are influenced by both environmental and genetic factors. Hereditary tumors are mainly caused by genetic factors. Examples of environmental factors for carcinogenesis are chemicals, smoking, ultraviolet light exposure, diet, viruses, and hormones

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Fig. 8.2
figure 2

Autosomal dominant inheritance pattern. Many hereditary tumors show an autosomal dominant pattern. Germ-line mutations are represented by (×). Fifty percent of the offspring of a mutantion carriers are also likely to carry mutations

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Fig. 8.3
figure 3

Two-hit theory (Knudson’s hypothesis). This hypothesis was based on statistical models from retinoblastoma patients. In this representation, two hits are required for carcinogenesis. Carriers of hereditary germ-line mutations already harbor the first ‘hit’ and the second hit follows after birth

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Fig. 8.4
figure 4

Hereditary and non-hereditary tumors. A comparison of hereditary vs. sporadic (non-hereditary) tumors. Hereditary tumors have different characteristics than sporadic tumors; multiple affected persons can be found in the pedigree. Moreover, onset at a younger age, multiple tumors, and bilateral tumors can occur. This phenomenon can be explained by the two-hit theory

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8.3 Hereditary Gynecologic Cancers

Hereditary gynecologic cancers involve HBOC, Lynch syndrome, PJS, Cowden syndrome and Li–Fraumeni syndrome. Table 8.1 presents a list of hereditary gynecologic cancers with related tumors and associated genes.

Table 8.1 Hereditary gynecologic cancers
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8.4 Hereditary Breast and Ovarian Cancer

Pathogenic germ-line variants in BRCA1/2 produce an increased risk of cancer in the breasts, ovaries, fallopian tubes, peritoneum, prostate, and pancreas. Individuals with male breast cancer are more commonly associated with families in which mutations in BRCA2 are more prevalent compared with BRCA1. Mutations in BRCA1/2 should be suspected in individuals with a personal or family history (i.e., in a first-, second-, or third-degree relative in either lineage) on the basis of any of the criteria listed in Table 8.2 [2].

Table 8.2 Factors in the clinical diagnosis of hereditary breast and ovarian cancer [2]
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Approximately 10–15% of patients with ovarian cancers harbor BRCA1/2 germ-line mutations [3, 4]. Table 8.3 shows the lifetime risk for HBOC-related cancers in patients who carry BRCA1/2 mutations [2]. Hence, gynecologists are likely to frequently encounter patients who are BRCA1/2 germ-line mutation carriers. Therefore, gynecologists who work in primary care are required to evaluate the genetic risks of HBOC in their patients and families.

Table 8.3 The lifetime risk for hereditary breast and ovarian-related cancers in individuals carrying pathogenic variants of BRCA1/2 [2]
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Ovarian serous carcinoma is frequently observed in BRCA1/2 mutation carriers, and ovarian cancers with BRCA1/2 mutations have been reported to exhibit unique chemosensitivity and prognosis [5,6,7]. For example, recently developed PARP inhibitors are more effective against BRCA1/2-mutated ovarian cancer [8]. Therefore, BRCA1/2 genetic testing is increasingly being performed in conjunction with companion diagnostics.

8.5 Lynch Syndrome

Lynch syndrome is caused by germ-line mutations in the mismatch repair (MMR) genes; MLH1, MSH2, MSH6, or PMS2. These mutations increase the risk of colon cancer as well as cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. Table 8.4 lists the characteristics of individuals with Lynch syndrome [2]. Colorectal and endometrial cancers are frequently found among carriers of MMR genes mutations, followed by gastric and ovarian cancers. While the risks of other Lynch syndrome-related cancers are lower, they remain elevated compared to the general population. Microsatellite instability (MSI) within tumor tissues and lower or absent expression of proteins encoded by MMR genes increase the probability of developing Lynch syndrome. Therefore, MSI or protein expression with immunohistochemistry (IHC) of MMR genes are frequently employed to screen Lynch syndrome before genetic testing of MMR genes.

Table 8.4 Cancer risks in individuals ≤70 years with Lynch syndrome compared to the general population [2]
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8.6 Detecting Hereditary Tumors in Clinical Practice and Introducing Genetic Counseling

It is important for a primary care physician to determine the family histories of individuals with hereditary tumors; therefore, thorough interviews are necessary. If the primary physician suspects that a patient’s tumor is hereditary in nature, screening of the patient’s family should be considered, at least up to second-degree relatives (i.e., grandparents, uncles, aunts, nephews, nieces, and grandchildren). Moreover, genetic counseling is recommended in such cases [9, 10].

The American Congress of Obstetricians and Gynecologists has released criteria for identifying patients who are predisposed to HBOC, and for whom genetic risk assessment is recommended [11]; Table 8.5 lists these criteria. Furthermore, the Amsterdam II Criteria are applied for the clinical screening of Lynch syndrome (Table 8.6) [12]. MSI and/or IHC tests can be performed in patients suspected of having Lynch syndrome. Finally, genetic testing for BRCA1/2 or MMR genes can differentiate the diagnosis of HBOC or Lynch syndrome.

Table 8.5 Criteria for genetic risk assessment by the American Congress of Obstetricians and Gynecologists [11]
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Table 8.6 The Amsterdam II criteria for the clinical screening of Lynch syndrome [12]
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8.7 Cancer Prevention and Risk Reduction Strategies

The endpoint of hereditary tumor research is to reduce mortality for cancers in mutation carriers who are at risk. RRSO is recommend for BRCA1/2 mutation carriers. RRSO reduces the risk of ovarian cancer for unaffected BRCA1/2 mutation carriers by 71–96% [13,14,15,16,17,18], and is usually performed after the completion of childbearing and during premenopausal years. However, premenopausal bilateral oophorectomy produces adverse effects; early-stage menopausal symptoms such as hot flashes, fatigue, shoulder stiffness, and palpitations can give rise to coital pain, atrophic vaginitis, urethritis, urinary incontinence, skin atrophy, and obesity. Long-term problems, such as osteoporosis or osteopenia, dyslipidemia, and arteriosclerosis, can also occur. Such adverse effects require monitoring by physicians who work on women health care [19].

Furthermore, according to recent NCCN guidelines, RRSO is also recommend in mutation carriers of MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM), and is considered in mutation carriers of RAD51C, RAD51D and BRIP1 [20].

8.8 Current State of HBOC Research

Recently, multi-gene assaying has been introduced that can analyze that status of multiple suspect genes simultaneously. Furthermore, genetic testing for hereditary tumors is applied not only for assisting in cancer diagnosis but also for companion diagnostics. BRCA1/2 testing is used as a companion diagnostic for PARP inhibitors. Furthermore, MSI screening may be used to predict the sensitivity of PD-1 (anti-programmed death-1) antibody because significant responses of cancers with MSI to anti–PD-1 inhibitors in patients who failed conventional therapy [21].

Conclusion

If clinicians suspect that an unusual number or pattern of cancers within a family may be caused by an inherited cancer predisposition genes, genetic counseling can be provided and genetic testing can be offered to find out inherited cancer genes. Gynecologists can play key roles in identifying women with hereditary cancer syndrome; this may help reduce mortality for mutation carriers.