Hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colon cancer syndrome are the two most important syndromes responsible for inherited cancers in gynaecology. Genetic testing is available for both these syndromes. Breast cancer gene testing is affordable and easy in women with ancestry where the mutation patterns are known, whereas other population groups need full gene screening. Hereditary non-polyposis colon cancer syndrome can now be diagnosed more frequently with the use of immunohistochemistry. Ovarian cancer risk is high in hereditary breast and ovarian cancer syndromes, and advanced screening techniques should be used when preventive surgery is not an option. Early detection techniques offer less protection than prophylactic removal, but enable women to retain their reproductive organs. Oophorectomy has the advantage of reducing breast cancer risk. In colorectal cancer syndromes, the risk for endometrial and ovarian cancer is much elevated. These risks should be recognised and addressed as these diseases are easy to prevent.
Introduction
Female lower genital tract cancers are strongly linked to infection with carcinogenic papilloma viruses. Cancers of the upper genital tract are linked to different risk factors, of which family history of related cancers or genetic risk is the strongest independent predictor. Between 5 and 15% of ovarian and uterine cancers are directly attributable to inherited mutations in high penetrance cancer predisposition genes.
If genetic risk factors are recognised and correctly managed, the chance of the individual developing and dying from cancer should be lowered. The identification of genetic risk depends strongly on obtaining and correctly interpreting the family history. In addition to an excess of cancer cases in the family history, certain disease phenotypes indicate that malignancy may have developed due to an inherited disorder. Examples include bilateral or triple negative breast cancer, synchronous uterine and ovarian cancer, and bilateral breast cancer.
Risk reduction must include both strategies to improve cancer survival by early detection (intensified screening and hopefully down-staging) and strategies to prevent the development of cancer (prophylactic medical and surgical measures or primary prevention). It is uncommon to diagnose cancer precursor disease in the upper tract; therefore, secondary prevention usually does not apply.
It is not possible to discuss screening for women with inherited cancer predisposition without also addressing other risk-reducing strategies. Although the focus will be on screening for gynaecologic cancers in this review, I will also briefly discuss other risk-reducing measures.
Breast cancer is an important part of cancer syndromes related to gynaecologic cancer. Breast cancer diagnosis in the woman or her family as a significant marker of genetic risk for gynaecologic cancer will be addressed. Reduction of breast cancer risk is an important aim for these women, and breast screening is addressed in the chapter by Panieri in this issue of Best Practice and Research Clinical Obstetrics and Gynaecology , with a focus on breast cancer screening in developing countries.
Identification of possible genetic predisposition
The diagnosis and management of families and individuals with cancer predisposition syndromes are complicated. Detailed knowledge and understanding of clinical genetics, gynaecology and psychology, as well as experience in counselling, cancer risk evaluation, prevention and screening techniques, are all essential. Management by a multi-disciplinary team skilled in all the above-mentioned aspects is highly recommended.
On the other hand, it is acknowledged that women and their families are often recognised and treated appropriately at generalist level by well-informed healthcare workers. Specialist genetic counselling services are not widely available in all parts of the world and, when available, it is often limited to large centres. Genetic testing is unaffordable for most people in the world. All gynaecologists should have at least basic knowledge of the related cancer syndromes and of cancer risk-management strategies. Diagnostic options should include genetic testing as well as probability diagnosis and risk assessment.
Cancer syndromes
Cancer is, by nature, a disease of accumulated genetic abnormality in the cells. The genes most often mutated in cancer cells are those responsible for the regulation of cell growth and division. Some of these genes are also commonly involved in inherited cancer syndromes, and then mutated in all germ-line cells. Many scarce genetic disorders may increase cancer risk, but the two important syndromes responsible for most inherited cancers in the gynaecologic organs are hereditary breast and ovarian cancer (HBOC) syndrome, including site-specific ovarian cancer syndrome, and hereditary non-polyposis colon cancer (HNPCC) syndrome, also named Lynch syndrome.
Hereditary breast and ovarian cancer syndrome
Genetic mutations in the BRCA1 (chromosome 17p) and BRCA2 (chromosome 13q) genes are found in most families (around 85%, depending on the criteria used), with a pattern of inherited cancer of the breast, ovaries, or both. Both these high-penetrance genes encode for tumour-suppressor proteins, and more than 1200 different mutations have been described in each large gene. Mutations will inactivate the protein product partially, leading to increased susceptibility to endogenous and exogenous carcinogens.
Mutation patterns are strongly population-specific, and inheritance is autosomal dominant, with varying penetrance of disease. The prevalence of BRCA mutations differs per population group, and many groups display a founder effect, enabling cheaper meaningful gene testing.
The BRCA genes do not explain all families with HBOC or site-specific ovarian cancer syndrome, and it seems more than likely that other genes, hitherto unidentified, are also important. Specifically, families displaying an excess of breast cancer only, will often not harbour a BRCA mutation. The other involved genetic factors may be recessive (as suggested by the excess in sibling compared with offspring risk), or may be dominant but with a smaller penetrance than the BRCA genes.
Hereditary non-polyposis colon cancer syndrome
Hereditary non-polyposis colon cancer syndrome, originally named Lynch syndrome, is caused by autosomal dominantly inherited germline mutation in one of the genes involved in the DNA mismatch repair ( MMR ) pathway. The three most common genes involved are MLH1 , MSH2 and MSH6 , and mutations predispose mainly to gastrointestinal (e.g. colorectal, stomach, small bowel, pancreas), uro-gynaecologic (e.g. renal, endometrial, ovarian) and brain cancer.
Importantly, in women from these families, the most common cancer is endometrial cancer (usually reported as ‘uterine’) followed by colorectal cancer. Mutations in these genes also explain about 10% of families with a pattern of inherited ovarian cancer.
Markers of genetic predisposition
Family history
Basic questions about the family history of related cancer will detect most families who harbour a mutation in one of the high-prevalence cancer predisposition genes. Family history remains the backbone of risk calculation to determine the appropriateness of gene testing and estimate the probability of an inherited susceptibility. The total incidence of related cancers are taken into account, and the occurrence of more unusual disease phenotypes will add more to the calculated risk of genetic predisposition.
In this way, the diagnosis of ovarian cancer, being a less common neoplasm, is a stronger predictor of mutation in the family than breast cancer. Breast cancer diagnosed before the age of 40 years, in multiple family members or bilaterally, is also more predictive of HBOC syndrome.
Male breast cancer is another important marker for HBOC families. The chance for BRCA2 mutation in an unselected man with breast cancer (without a family history) is estimated between 5 and 20%, and BRCA1 may also cause the disease. Any man with breast cancer with a family history of breast, ovarian cancer, or both, has a risk for BRCA mutation of more than 50%. It is in the interest of family members to refer all men with breast cancer for genetic counselling and testing where available, and BRCA2 should be the first gene to test. The important diagnostic markers of HBOC families are listed in Table 1 .
