Fig. 8.1
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
Fig. 8.2
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
Fig. 8.3
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
Fig. 8.4
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
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
Syndrome | Related tumors and typical phenotype | Associated gene |
|---|---|---|
Hereditary breast and ovarian cancer syndrome | Breast cancer (including male breast cancer) | BRCA1 |
Ovarian cancer, fallopian tube cancer, peritoneal cancer | BRCA2 | |
Prostate cancer | ||
Pancreatic cancer | ||
Lynch syndrome | Colorectal cancer | MSH2 |
Endometrial cancer | MLH1 | |
Ovarian cancer | PMS2 | |
Small intestinal cancer | MSH6 | |
Renal pelvic, or ureteral cancer | ||
Gastric cancer | ||
Hepatobiliary cancer | ||
Sebaceous neoplasms of the skin in Muir-Torre syndrome | ||
Peutz-Jeghers syndrome | Gastrointestinal polyposis | STK11 |
Mucocutaneous pigmentation | ||
Colorectal, stomach and small bowel cancers | ||
Adenoma malignum of the cervix | ||
Sertoli cell tumors of the testes | ||
Sex cord tumors with annular tubules | ||
Ovarian tumor | ||
Breast cancer | ||
Pancreatic cancer | ||
Cowden syndrome | Breast cancer | PTEN |
Thyroid cancer | ||
Macrocephaly | ||
Endometrial carcinoma | ||
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].
Breast cancer diagnosed at the age of 50 years or younger |
Ovarian cancer |
Multiple primary breast cancers in either the same or contralateral breast |
Comorbid breast and ovarian cancers |
Male breast cancer |
Triple-negative (estrogen receptor negative, progesterone receptor negative, and HER2 negative) breast cancer |
Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family |
Ashkenazi Jewish ancestry |
Two or more relatives with breast cancer, one under the age of 50 |
Three or more relatives with breast cancer at any age |
A previously identified BRCA1 or BRCA2 pathogenic variant in the family |
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]
Cancer type | Risk (%) |
|---|---|
Breast cancer | 40–80 |
Ovarian cancer | 11–40 |
Male breast cancer | 1–10 |
Prostate cancer | Up to 39 |
Pancreatic cancer | 1–7 |
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 [5–7]. 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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