Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 24, Issue 1 , Pages 3-18, February 2010

Cancer genetics and reproduction

  • Helen Hanson, MBBS, MRCP (Clinical Research Fellow)

      Affiliations

    • Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK
    • Corresponding Author InformationCorresponding author. Tel.: +44 208 722 4000; fax: +44 208 722 4359.
    • ,
  • Shirley Hodgson, BM BCh, DM, FRCP (Professor of Cancer Genetics)

      Affiliations

    • Department of Clinical Genetics, St Georges Hospital, Blackshaw Road, Tooting, SW17 ORE, UK
    • Tel.: +44 208 725 5279, Fax: +44 208 725 3444.

published online 28 August 2009.

Article Outline

Cancers of the reproductive organs (i.e., ovaries, uterus and testes), like other cancers, occur as a result of a multi-stage interaction of genetic and environmental factors. A small proportion of cancers of the reproductive organs occur as part of a recognised cancer syndrome, as a result of inheritance of mutations in highly penetrant cancer susceptibility genes (e.g., BRCA1, BRCA2, MLH1 or MSH2). Recognition of individuals and families with inherited cancer predisposition syndromes and individuals at high risk due to familial cancer clustering is fundamentally important for the management and treatment of the current cancer and for future prevention of further cancers for the individual and their extended family.

Keywords: hereditary cancer syndrome, ovarian cancer, endometrial cancer, BRCA1, BRCA2, MLH1, MSH2, hereditary non-polyposis colon cancer, lynch syndrome

 

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Introduction 

Over the past two decades, significant advances have been made in our understanding of cancer genetics. Familial clustering of cancer has been recognised since Roman times; however, it is only now we are beginning to appreciate the true role of genetic factors in cancer susceptibility. Tumour suppressor genes acting in accordance with Knudson's two-hit hypothesis were first described for retinoblastoma.1 The tumour suppressor genes, BRCA1 and BRCA2, were cloned following genome-wide linkage analysis in the 1990s2, 3 after the recognition of autosomal dominant transmission of breast and ovarian cancer in large families.

With increasing knowledge of molecular pathways, genes within an appropriate biological pathway can be directly interrogated within families with cancer clustering. This candidate gene approach, exemplified by the verification of germ line TP53 mutations in the Li–Fraumeni syndrome,4 has led to identification of further susceptibility genes. This is most notable in breast cancer susceptibility, with the identification of mutations in the DNA repair genes BRIP1, CHEK2 and PALB2, which confer a moderate increase in risk of breast cancer (Relative risk 2–4).5, 6, 7

However, in practice, these low-prevalence, moderate to high-penetrance, cancer susceptibility genes account for only a small proportion of hereditary cancer. Emerging evidence suggests that the majority of familial clustering of some cancers may be explained by several lower-penetrance genetic variants and recent years have witnessed the emergence of genome-wide association studies. In these studies conducted for both cancer and other common complex diseases, the frequency of a specified variant is compared in cases and controls. With detailed maps of the human genome, including maps of single nucleotide polymorphisms (a single base change in DNA), extensive analysis of thousands of common variants within the genome, between cases and controls, can be performed. In large case-control studies, associations between common variants and disease are recognised, although in practice each variant is associated with only a small increase in relative risk of the disease. This approach has led to the discovery of common genetic variants, which are believed to act multiplicatively to increase cancer susceptibility. This has been demonstrated for breast and prostate cancer8, 9, 10, but may prove difficult for unexplained familial ovarian and endometrial cancer, as they occur more rarely in the general population, making large-scale studies less feasible.

Consequently for cancers of the reproductive organs, current clinical practice should comprise identification and appropriate management of individuals at risk of highly penetrant cancer predisposition syndromes, through both gynaecology and clinical genetics. In future years, accurate characterisation of an individual's risk for a particular cancer type, based on a panel of genetic polymorphisms may be within reach.

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Recognition of cancer syndromes 

In the recognition of cancer syndromes, two scenarios may be encountered: either the observation of clustering of a specific type of cancer within a family (e.g., breast or colon cancer) or the occurrence of a number of different cancers in family members, representing a defined cancer syndrome (e.g., sarcomas, breast cancer and brain tumours in the Li–Fraumeni syndrome).

The cardinal features of hereditary cancer syndromes include early age of cancer diagnosis, bilateral cancers, multiple primaries and multiple affected family members, spanning a number of generations.

Approximately 5% of all cases of endometrial cancer and 10% cases of ovarian cancer are due to inherited mutations in high-penetrance, low-prevalence cancer susceptibility genes.11 The majority of these cases are due to two recognised cancer syndromes: hereditary breast–ovarian cancer (HBOC) syndrome or hereditary ovarian cancer (HOC) syndrome, associated with germ-line mutations in BRCA1 and BRCA2 and Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), associated with mutations in the DNA mismatch repair (MMR) genes (Table 1, Table 2).

Table 1. Cancer syndromes associated with ovarian cancer [12, *13, 14, 15, 16, *17, 18, 66].
SyndromePercentage of Hereditary Ovarian CancerTypical HistologyGeneLifetime Ovarian Cancer Risk (General population risk <2%)
Hereditary breast and ovarian cancer syndrome/Hereditary ovarian cancer syndrome90%Epithelial - predominantly serous.BRCA139–63%
BRCA211–27%

Lynch Syndrome5%–10%Epithelial, predominantly serous, other epithelial histology also observed.Mismatch Repair Genes (MLH1, MSH2, MSH6, PMS2)12%

Gorlin Syndrome<1%Ovarian fibromas or (rare) fibrosarcomas.PTCH<2%

Peutz Jeghers Syndrome<1%Sex cord-stromal tumours particularly ovarian sex-cord tumour with annular tubules (SCTAT).STK1118% (all gynaecological malignancy)
Table 2. Cancer syndromes associated with endometrial cancer [18, 19, 20].
SyndromeGeneLifetime endometrial cancer risk
Lynch SyndromeMMR Genes (hMLH1, hMSH2, hMSH6 and PMS2)30–60%
Cowden SyndromePTEN5–10%

In some hereditary cases, clinical genetic testing and identification of a causative pathogenic mutation are possible. However, in a subset of seemingly hereditary cases, no mutation is identified and the familial clustering is likely to be accounted for by a combination of environmental factors and low-risk alleles or genetic polymorphisms acting together to increase susceptibility to certain cancers, which has yet to be fully understood.

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Hereditary Breast and Ovarian Cancer (HBOC) syndrome 

HBOC syndrome is typified by four or more breast or ovarian cancers within a family, typically occurring at young ages or bilaterally in the case of breast cancer. Ovarian cancers are typically epithelial, with a younger age of onset in BRCA1 carriers (mean: 54 years), compared with sporadic ovarian cancers (mean: 63 years), which have a comparable age of onset to BRCA2 carriers (mean: 62 years).13 Breast cancer in these families is also typically seen at younger ages, particularly in BRCA1 carriers, compared with that in the general population (Fig. 1, Fig. 2).

Identification of BRCA1 and BRCA2 

BRCA1 was cloned on chromosome17q21 in 1994, following a long search for the gene using linkage analysis.2 This was closely followed by discovery of BRCA2 on chromosome 13q12–13 in 1995.3 Both are classic tumour suppressor genes, requiring loss of both alleles in the susceptible tissue for progression of tumourigenesis. Both genes are involved in the maintenance of genomic stability by facilitating DNA repair, primarily executing DNA double-strand break repair by homologous recombination. This property is now a target for therapeutic exploitation in the treatment of breast and ovarian cancer in women with inherited BRCA1 and BRCA2 mutations, with both platinum-based chemotherapy that induces double-strand DNA breaks and PARP inhibitors, which exploit the role of BRCA1 and BRCA2 in DNA repair.

Despite BRCA1 and BRCA2 initially appearing to be genes with similar functions, it is now clear that the two genes are different in terms of their molecular biology, protein interactions and the cancer risks they confer.21

Contribution of BRCA1 and BRCA2 mutations to familial ovarian cancer 

Most studies looking at the contribution of germ line BRCA1 and BRCA2 mutations to familial ovarian cancer have ascertained families due to clustering of breast rather than ovarian cancer cases. One large study, which first reported in 1999 and was recently revisited, ascertained families due to ovarian cancer clustering. They found the proportion of families with a mutation varied according to family history. In families with at least three close relatives with epithelial ovarian cancer, 63% were found to have a mutation in BRCA1 or BRCA2, with the majority of mutations occurring in BRCA1.22, *23 Mutation frequency increased in families who also had cases of breast cancer, diagnosed before age 60 years and increasing numbers of ovarian cancers. In families with only two cases of ovarian cancer and no breast cancer, only 27% were found to have a mutation in one of the two genes, whereas in families with at least two ovarian and two breast cancer cases, BRCA mutations were detected in 83% families. In families without a detected mutation, it is possible that some mutations were missed due to insensitivity of detection method and mutations in the MMR genes, will account for further families. However, a proportion of site-specific familial ovarian cancer remains unexplained. As yet no single gene that confers increased susceptibility to ovarian cancer alone has been identified. It is possible that families with only two cases may be explained either by chance or inheritance of several lower susceptibility genes.

Contribution of BRCA1 and BRCA2 mutations to isolated ovarian cancer 

Women with ovarian cancer or their close relatives are often concerned about genetic risk, due to the aggressive nature of ovarian carcinomas and the difficulty with early detection. A number of studies have been performed to assess the prevalence of BRCA1 and BRCA2 mutations in population series of ovarian cancer cases, unselected for family history.11, 16, 24, 25 However, there are flaws in study design, including small numbers, patient ascertainment, lack of detailed family history on maternal and paternal sides or inclusion of women with founder mutations. Consequently, estimates of mutation prevalence in ovarian cancer overall, vary between 2% and 9% in studies for BRCA1 and 1% and 6% for BRCA2.

Currently, the National Institute for Health and Clinical Excellence (NICE) guidelines recommend BRCA testing for individuals with ovarian cancer if there is a further case of ovarian cancer or breast cancer diagnosed below 50 years within the close family, but not in an isolated case.

Penetrance of BRCA1 and BRCA2 mutations 

Inherited mutations in BRCA1 and BRCA2 are highly penetrant. However, estimations of cancer risk in mutation carriers vary between studies, mainly due to ascertainment bias. Early studies calculated risk from small numbers of large cancer families, and suggested that women with mutations in BRCA1 have up to an 87% lifetime risk (defined as risk up to age 70) of breast cancer and up to a 63% lifetime risk for ovarian cancer. Whilst women with mutations in BRCA2 have a comparably elevated lifetime risk of breast cancer of up to 84%, the degree of ovarian cancer risk is lower with lifetime risks of up to 27%.15, 26 Male breast cancer, pancreatic cancer, prostate cancer and melanoma are more frequently observed in BRCA2 mutation carriers than in the general population.27 In BRCA2, a higher risk of ovarian cancer is associated with mutations occurring in the ‘ovarian cancer cluster region’ in exon 11.28

Notably in population-based studies of BRCA1 and BRCA2 mutation carriers unselected for family history, the estimated cancer risks are significantly lower. In a combined analysis of 22 studies in which BRCA1 and BRCA2 carriers had been identified independently of their family history, ovarian cancer lifetime risk was estimated at 39% for BRCA1 carriers and 11% for BRCA2 carriers.12 The higher penetrance figures determined in earlier studies are partly explained by ascertainment bias from large families with multiple cancer cases.

The variance in penetrance estimates between studies are also partly explained by modifying environmental factors such as breast feeding, parity and hormonal factors, as well as low-penetrance genetic variants, which can cluster in families. Thus, families with large numbers of affected individuals may have clustering of other genetic variants, each conferring a small increase in risk, in addition to BRCA1 and BRCA2, explaining the higher penetrance estimates from the original studies that included families with multiple cancer cases.

Genome-wide association studies have identified common alleles, which are associated with increased breast cancer risk in the general population8, and further work has demonstrated that some of these act multiplicatively to alter breast cancer risk in BRCA2 carriers, but the evidence is not so strong for interaction with BRCA1.30 Similar genetic interactions need further clarification for ovarian cancer risk.

BRCA1 and BRCA2 Founder mutations 

The Ashkenazi Jewish population is host to a number of founder mutations for inherited conditions. Three founder mutations occur in the BRCA genes: 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Up to 60% of ovarian cancer31 and 30% of early-onset breast cancer in this population is due to one of these mutations.32, 33 Approximately 1 in 40 Ashkenazi Jews are mutation carriers.34 Consequently, mutation analysis of these three founder mutations can be performed in unaffected women with a family history of breast or ovarian cancer and Ashkenazi heritage.

Founder mutations have also been described in Northern European, French-Canadian and other populations.35

Histology of ovarian cancer in BRCA1 and BRCA2 carriers 

The majority of ovarian cancers occurring in women carrying germ-line mutations in BRCA1 or BRCA2 are diagnosed at a younger age, are high grade and advanced-stage serous carcinomas.*13, 16, 36, 37 Epithelial serous ovarian carcinoma is the most common histological subtype and is found in up to 90% of all cases.16, 25 Endometrioid carcinomas account for most of the remaining cases, with other epithelial tumours occurring occasionally. Papillary serous peritoneal tumours and fallopian tube cancers should be considered as part of the tumour spectrum in women carrying BRCA1 or BRCA2 mutations.38

Mucinous tumours are generally not thought to be characteristic of ovarian cancers in BRCA1 or BRCA2 mutation carriers25, 37, but are associated with HNPCC/Lynch syndrome. Similarly, borderline tumours of the ovary are also not characteristic of cancers in BRCA1 or BRCA2 mutation carriers.37, 39 Germ cell tumours and sex-cord stromal tumours are not characteristically seen in women with BRCA1 or BRCA2 mutations. If there is a family history of cancer, an ovarian tumour of this histology should prompt consideration of another cancer syndrome, such as Peutz–Jeghers syndrome.

Prognosis of ovarian cancer in BRCA1 or BRCA2 carriers 

Ovarian cancers occurring in women with BRCA1 or BRCA2 mutations are generally of a higher stage and grade at diagnosis compared with sporadic cancers. Some studies suggest that hereditary ovarian cancers have been found to have a better clinical outcome*13, 36 with improved survival40 and recurrence-free interval after chemotherapy than sporadic cancer. However, not all studies agree with this, with some studies suggesting poorer survival.41, 42 In addition, the studies suggesting better survival have been criticised for selection bias. Improved survival could be due to the increased sensitivity of BRCA-deficient tumour cells to DNA-damaging agents such as cisplatin, which induce double-strand DNA breaks.

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Lynch syndrome 

The clustering in families of colon cancer, often also with cases of ovarian, endometrial, gastric, transitional cell carcinomas of the urological tract and biliary tract cancers, typify Lynch syndrome (LS) or HNPCC (Fig. 3).43 Colonic carcinomas in LS/HNPCC are typically diagnosed at an early age, and predominantly occur in the proximal colon. The risk for individuals with LS/HNPCC of developing colon cancer is approximately 80% by age 70.18 The modified Amsterdam criteria44 are used clinically to identify families suitable for molecular testing and are more widely used than the original Amsterdam criteria, which do not take into account the extra-colonic malignancies.45

Genetics of Lynch Syndrome 

Inherited mutations in a set of genes known as the mismatch repair genes are responsible for LS/HNPCC. These genes are responsible for repair of nucleotide mismatches and insertion–deletion loops during DNA replication.

Loss of function in the MMR pathway results in microsatellite instability in tumour cells, the hallmark of LS/HNPCC, identified by the presence of extra repeats at a DNA microsatellite in the tumour, when compared with normal DNA (microsatellites are stretches of DNA in which a series of nucleotides are repeated).

Mutations in MLH1 and MSH2 account for 70–90% of germ-line mutations46 in LS families, mutations in MSH6 account for approximately 10% but mutations in PMS2 and PMS1 are also occasionally found.47, 48

LS is most frequently diagnosed by gastroenterologists, due to the predominance of colon cancer in this condition. However, a retrospective multicentre study49 of women with LS and both gastrointestinal and gynaecological cancer found that, in 51% of cases, women presented with a gynaecological cancer and 49% presented with gastrointestinal cancer. Consequently, it is important for gynaecologists to recognise the cardinal features of this syndrome.

The Amsterdam criteria were originally used to define LS/HNPCC families for research purposes, and classify a family clinically. They serve as a good discriminator for germ-line MMR mutations, with mutations identified in approximately 50% families fulfilling these criteria50, but are not very sensitive, so the criteria were later widened to include extracolonic cancers in the “modified Amsterdam criteria” (Table 3). However, it is widely recognised that families not meeting even the modified criteria may have germ-line MMR mutations, so the Amsterdam criteria may not be sensitive or specific enough to use in isolation. Therefore, analysis for microsatellite instability (MSI) in tumour samples may be performed in some families first as a screening test, because although MSI may be seen in about 15% of sporadic colorectal cancers, the majority of colon cancers in individuals with LS/HNPCC are MSI-high. It is also important to be aware of ‘red flag’ features in one individual, such as synchronous or metachronous cancers, or young age at diagnosis.

Table 3. Amsterdam Criteria.
Modified Amsterdam Criteria [44]
At least 3 relatives with a Lynch Syndrome/HNPCC cancer (colorectal, endometrial cancer, small bowel cancer, ureter or renal pelvic cancer) in one lineage;
One affected individual should be a first degree relative of the other two
At least two successive generations affected
At least one HNPCC associated cancer should be diagnosed before 50

Association with ovarian cancer 

The lifetime risk of ovarian cancer in LS is estimated to be 9–12%.18, 51, 52 The mean age at diagnosis, 43 years, is slightly younger than carriers of BRCA1 or BRCA2 mutations.17 In fact, ovarian cancer diagnosed at a very early age, is more likely to be due to germline MMR mutations than BRCA mutations.39 Population based studies, unselected for age or family history suggest that germline MMR mutations are found in 2% of ovarian cancer cases overall.11

Histologically, epithelial cases account for approximately 94% of cases and non-epithelial only 6%. Within epithelial cancers, the most common subtypes are papillary serous and endometrioid. Mucinous and clear cell cancers occur at a lower frequency. The overall distribution of subtype is similar to that seen within the general population, other than a slight increase in frequency of the endometrioid subtype.17

The risk of ovarian cancer is significantly increased in both MLH1 and MSH2 carriers, but highest in MSH2 families.53, 54

Association with endometrial cancer 

After colon cancer, endometrial carcinoma has emerged as the second most common cancer associated with LS. Female carriers of a mutation in an MMR gene have a lifetime endometrial cancer risk of 30–60%, depending on ascertainment of individuals studied.18, 19, 55, 56 Risk also varies with mutation type. MSH6 mutation carriers have a high risk (up to 70%) of endometrial cancer57, 58, but a lower risk of colorectal cancer, compared with women carrying mutations in the other genes. A recent study of 982 cancers in 130 individuals with MMR mutations also found MSH2 mutation carriers to have a high incidence of endometrial cancers, with familial clustering of endometrial cancer in some families with MSH2 mutations.53

The mean age at diagnosis of endometrial cancer in women with LS is in the fifth to early sixth decade of life*49, 55 compared to an average age of 66 years in the general population. MSH6 carriers may have a later age of onset, compared to MLH1 or MSH2 carriers.

Two population based studies, of young onset endometrial cancer cases, unselected for family history, both demonstrated that approximately 9% women with endometrial cancer under the age of 50 have mutations in one of the MMR genes.59, 60 However, the majority of these women also had a significant family history, consistent with LS. Consequently both studies established that the combination of endometrial cancer diagnosed below 50 years and a first degree relative with a LS associated cancer is more predictive of a MMR mutation (23–43%).

Synchronous or metachronous cancers 

It is well documented that patients with LS are at risk for multiple synchronous and metachronous tumours.18 Cancers in the LS spectrum occurring synchronously or metachronously should raise suspicions of LS/HNPCC, even in the absence of a family history of other cancers.

Approximately 20% women with both colon and endometrial cancer have an HNPCC mutation.61 The prevalence of MMR mutations in women with synchronous endometrial and ovarian cancers has been less well studied, but family history is suggestive in up to 6% cases.62 In women with confirmed LS and ovarian cancer, up to 22% have associated synchronous endometrial cancer.17

Familial endometrial cancer 

Occasional families show clustering of endometrial cancer alone, known as familial site-specific EC.63 The molecular basis of this syndrome is as yet unknown. A number of studies have attempted to address whether clustering of endometrial cancers in the absence of other cancers can be explained by mutations in MMR genes. A study in 23 families with site-specific EC found MMR gene mutations in two such families (8.7%)64, a figure comparable with the frequency of germ-line mutations in women with endometrial cancer selected for young age.60 Therefore, the simultaneous presence of colon or other gastrointestinal (GI) cancer with endometrial cancer in the proband or other close family members remains the stronger predictor of germ-line MMR mutations.60, 61

Additional studies may establish whether site-specific EC is due to heritable defects in other genes, environmental factors or chance.

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Other cancer syndromes 

Ovarian tumours can be seen in a number of other cancer syndromes to a lesser degree. These include Peutz–Jeghers Syndrome, an autosomal dominant disorder characterised by hamartomatous polyposis of the GI tract and mucocutaneous melanin pigmentation, associated with germ-line mutations in STK11. Cancers of the GI tract are unequivocally increased in this syndrome.65, 66, 67 Sex-cord stromal tumours of both testes and ovaries are also reported with increased frequency. Adenoma malignum of the uterine cervix is also rarely associated with this condition, probably due to the over-secretion of oestrogens by the stromal sex-cord ovarian tumours, which can occur in childhood.68

Gorlin syndrome is an autosomal dominant condition associated with basal cell carcinomas, jaw cysts and ovarian fibrosarcomas.69 Ovarian fibromas are common in Gorlin syndrome, but they are of low malignant potential. It is due to inherited mutations in the PTCH gene.

Cowden's disease is another autosomal dominantly inherited hamartomatous polyposis syndrome due to inherited PTEN mutations, characterised by multiple hamartomas, dermatological manifestations, macrocephaly and a predisposition to thyroid disease and breast tumours. There is also an increased risk of endometrial carcinoma, which forms part of the diagnostic criteria, but this is not a common feature of the condition.70 Gynaecological surveillance by annual transvaginal ultrasound and endometrial biopsy may be recommended in affected women.

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Management and diagnosis of a suspicious family history 

All families with strong or unusual family histories of cancer should be referred to a clinical genetics centre for clarification of family history and genetic counselling. A three-generation pedigree is the minimum required for accurate risk assessment, being aware that a BRCA1, BRCA2 or MMR mutation may be transmitted by an unaffected male in the case of breast, ovarian and endometrial cancers. An individual's paternal family history should always be taken. Confirmation of cancers is particularly important in the case of ovarian cancers, as many relatives reported to have stomach cancers may have in fact had an ovarian primary and, conversely, cervical cancers are often confused with ovarian or endometrial cancers.

Genetic testing-BRCA1 and BRCA2 

NICE guidance recommends analysis of BRCA1 and BRCA2 in families that have a 20% or greater chance of having a mutation. Models such as BOADICEA and BRCAPRO or empirical scoring systems such as the Manchester score71, 72, 73 can be used to identify families and individuals meeting this risk threshold, but good clinical judgement is also required as these models do not cover every scenario, including adopted individuals, small families and adjustment for environmental risks.

Hundreds of mutations have been reported in BRCA1 and BRCA2 and, although there is some clustering of mutations in exon 11 in both genes, mutations frequently occur outside this region, and targeted mutation analysis, other than for Jewish founder mutations, is not possible. Testing is performed by direct sequencing (to detect point mutations or small deletions or insertions) and MLPA (to detect genomic rearrangements, including exon deletions and duplications), which together identifies over 95% of mutations.

Diagnostic mutation analysis is normally only performed on family members affected with cancer.The most suitable individual in the pedigree is normally selected for diagnostic testing, based on age of cancer diagnosis, presence of bilateral breast cancer or breast and ovarian cancer in one individual, male breast cancer or proximity in the pedigree to other affected individuals. If a mutation is not identified in an affected individual the result is regarded as negative. A negative result indicates it is very unlikely there is an undetected BRCA1 or BRCA2 mutation in the family, due to the high sensitivity of the testing, provided an appropriate individual was tested. However, a negative result does not mean the cancers are not hereditary, and it is possible the familial risk is attributable to other factors, which may include other genetic or environmental factors. In this case, the family pedigree needs to be reviewed to determine an appropriate screening strategy for family members still considered to be at increased risk. If an unaffected person is offered diagnostic testing, prior to identification of a pathogenic mutation in an affected family member, a negative result will not be informative in determining the cause of the familial risk. An unaffected individual may not have inherited the pathogenic BRCA mutation from their parent or the familial risk may be due to other factors. Therefore, testing an unaffected individual is not normally performed unless the individual is of Ashkenazi heritage or other exceptional circumstances.

When a pathogenic mutation is found in a family, known as a positive result, other family members can be invited for predictive testing. Following genetic counselling, testing for the known familial mutation in BRCA1 or BRCA2 can be performed. If an unaffected woman is negative for the known familial mutation, she can be reassured she is not at high risk of developing breast or ovarian cancer. Women who are found to be positive for the familial mutation can be counselled regarding increased surveillance or prophylactic surgery.

Genetic testing–MMR genes 

In the selection of appropriate genetic testing for MMR genes, approximately 50% of families fulfilling the modified Amsterdam criteria have inherited MMR mutations50, and in these families, direct mutation analysis of MMR genes is possible. If the family history is suspicious but does not satisfy the Amsterdam criteria, tumour tissue (normally colon, but other tumours can also be examined) can be examined for microsatellite instability (MSI). Only 10–15% of sporadic colon tumours display MSI, and this is usually due to somatic hypermethylation of the hMLH1 promoter, whereas MSI is seen in up to 95% tumours in individuals with LS/HNPCC. A panel of five markers are used for the identification of MSI in tumours; MSI is classified as high where two or more of the panel demonstrate instability and MSI stable when no markers show instability.74

If MSI is demonstrated, immunohistochemistry (IHC) of the MMR genes can be performed on tumour tissue. Antibody staining for the main MMR proteins is performed. Absence of staining indicates that a specific MMR gene is not present, either due to mutation, or somatic loss, or methylation in the case of MLH1. Testing then proceeds to direct sequencing and MLPA of the appropriate MMR gene in constitutional DNA.

The Bethesda criteria75 were developed to identify families suitable for MSI analysis and increase the detection rate of patients with LS/HNPCC. Although MSI is the most discriminatory first-line investigation, IHC is often performed due to availability or cost and also has the advantage of directing germ-line mutation analysis.

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Management and treatment 

Prevention 

Oral contraceptives 

The chemopreventive benefits of the oral contraceptive pill (OCP) for ovarian cancer are well recognised in the general population, with a number of case control and cohort studies indicating a decreased risk of ovarian cancer with OCP use.76 The same effect has been observed for BRCA mutation carriers in one case-control study77, but not in another.78 The effect is unknown for women with LS.

However, the converse is true for the OCP and breast cancer risk in the general population, with a recognised small increased risk of breast cancer in users79, which would suggest that oral contraception should not be used as a chemopreventive agent for ovarian cancer in BRCA mutation carriers. In fact, the same group who reported the benefits of OCP for ovarian cancer risk reduction in BRCA mutation carriers also reported that oral contraceptive use is associated with an increased risk of breast cancer in BRCA1 mutation carriers80 when used before age 30 years and for more than 5 years' duration.

Prophylactic oophorectomy 

For women with a BRCA1 or BRCA2 mutation, prophylactic bilateral salpingoophorectomy (PBSO) is now confirmed as the most robust method of reducing ovarian cancer risk. Combined data from European and American centres indicate that the risk reduction for ovarian cancer is greater than 95%.81 The mean age of ovarian cancer in BRCA1 and BRCA2 mutation carriers is approximately 50 years, but the range varies from 30 to 70 years. The risk of ovarian cancer begins to increase earlier in BRCA1 mutation carriers, with 2–3% of women developing ovarian cancer by age 40 years, but the same percentage developing cancer by age 50 years in BRCA2 mutation carriers.82

In premenopausal women, PBSO has the additional benefit of reducing breast cancer risk by 50%.*81, 83 Although BRCA2 mutation carriers may wish to defer PBSO due to later onset of ovarian cancer, they may lose some of the additional benefit in reducing breast cancer risk if PBSO is not performed premenopausally. It would therefore seem appropriate to offer PBSO to all BRCA1 and BRCA2 mutation carriers once childbearing is complete.

The most serious side effects of PBSO are the symptoms associated with an induced surgical menopause, including hot flushes, vaginal dryness, sexual dysfunction and sleep disturbances, which women may see as a contraindication to surgery. In addition, women may be concerned regarding the use of hormone replacement therapy (HRT) and breast cancer risk.84 Fortunately, studies have shown that short-term HRT use in these women does not negate the protective effect of PBSO on breast cancer risk and can be used for treatment of symptoms associated with induced menopause.85, 86 Whilst short-term HRT use can be recommended for relief of menopausal symptoms, long-term use for protection against cardiovascular disease and osteoporosis remains largely unevaluated. Studies suggest that continuation of HRT after age 50, the age of natural menopause, irrespective of whether an individual has also had mastectomy are associated with decrements in life expectancy.86 Therefore, women should strongly consider discontinuing HRT use at this age.

Women with BRCA mutations are also at risk of primary peritoneal cancers and fallopian tube cancers, and these cancers along with occult ovarian cancers are occasionally observed in women undergoing PBSO.87 Recent reports suggest that the distal fallopian tube is a common site for occult disease in women undergoing PBSO and may actually account for the majority of malignancies previously attributed to primary ovarian or peritoneal cancer88. Due to this risk, both fallopian tubes and the adjacent peritoneum must be removed at surgery. ‘Bagging’ of the ovaries during removal, taking peritoneal washings for cytology and an extensive pathology review, including at a minimum, serial sectioning at 2-mm intervals of fallopian tube and ovaries should be performed. Most centres have strict protocols for PBSO and more stringent methods of examining the fimbria have been developed in light of the recent reports.89

In women with LS, it is reasonable to consider prophylactic hysterectomy and oophorectomy once childbearing is complete.51 It is advisable to perform endometrial biopsy prior to surgery due to the risk of occult cancer.90

Most of the epidemiologically observed familial co-occurrence of breast and ovarian cancer is accounted for by inherited BRCA1 and BRCA2 mutations.15, *23 Consequently, in ‘breast cancer only’ families in whom a deleterious mutation in BRCA1 or BRCA2 has not been identified, there is no evidence to suggest an increased risk of ovarian cancer. A recent study91 demonstrated an expected increased risk of breast cancer in BRCA-negative, site-specific hereditary breast cancer families, but no significantly increased risk of ovarian cancer. Breast cancer in these families is most likely due to the multiplicative effects of lower-penetrance genes92, which may not be associated with ovarian cancer risk. However, PBSO may still have a role in these women for breast cancer prevention and this will need further evaluation.

Ovarian screening 

In all screening programmes, the goal is to identify tumours at an earlier age. Unfortunately, the efficacy of screening for ovarian cancer using transvaginal ultrasound (TVU) and serum CA125 measurement is currently of unproven benefit. No currently available ovarian cancer screening has yet demonstrated adequately the fundamental attributes of a screening test to justify the routine use in the general population or in individuals at high risk. Problems include the high occurrence of interval cancers and the advanced stage of ovarian cancers that are screen detected. The UKFOCSS study is currently evaluating the use of serial CA125 measurements and ovarian ultrasound in women at high risk (lifetime risk >10%), and the results should provide definitive evidence of the benefit of screening. A more promising screening method may be identification of new novel biomarkers to improve screening efficacy. Ovarian screening was recently the subject of a review in this journal and will not be covered in further detail here.93

Endometrial screening 

Two studies with varying conclusions have been published regarding the efficacy of endometrial screening by TVU in women with LS.94, 95 Dove Edwin concluded after a prospective trial of annual TVU in 269 women that this was not an adequate screening method for detection of endometrial cancer; however, the other study felt that ultrasound had led to detection of premalignant lesions and was warranted. Cancers were detected outside the screening programme in both the studies.

A recent study from Finland96 has demonstrated that screening with TVU and aspiration biopsy does increase the detection of early atypical endometrial hyperplasia and cancer and provides good evidence that this method of screening is helpful.

The value of surveillance for endometrial cancer still warrants further studies. TVU and endometrial aspiration biopsy from age 30 to 35 years may be beneficial in detection of premalignant lesions and is recommended in the USA and suggested in the recent guidelines by Vasen et al.50

Prophylactic hysterectomy 

With the limitations of endometrial screening, women with LS, who have completed their families, may choose to undergo total abdominal hysterectomy and PBSO. The effectiveness of hysterectomy and hysterectomy with PBSO are emerging as a robust method of decreasing gynaecological cancer risk in LS97, 51; As for BRCA carriers it seems appropriate to offer prophylactic surgery once childbearing is complete. However due to the large number of cancer types associated with LS, MMR mutation carriers may die from other malignancies, despite prophylactic gynaecologcial surgery.51

Treatment 

Treatment for inherited cancers is currently an area of significant development. It is hoped that using new knowledge regarding cancer development and genetics, individualised treatment strategies will be developed for women, depending on the driving genetic factors of their cancer.

PARP inhibitors 

PARP inhibitors are an exciting development in the treatment of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. They act as a targeted treatment specifically against cancers occurring in women carrying mutations in the BRCA1/2 genes, where the cancer is assumed to be null for function of the relevant BRCA gene. BRCA1 and BRCA2 are involved primarily in DNA double-strand break repair by homologous recombination, whilst PARP is involved in base excision repair, a key link in the repair of DNA single-strand breaks. The absence of PARP activity, induced by a PARP inhibitor, leads to spontaneous single-strand breaks, which collapse replication forks into double-strand breaks. Thus, cancer cells deficient in BRCA1 or BRCA2 function are unable to perform homologous recombination, and the resulting effect is chromosomal instability, cell cycle arrest and subsequent apoptosis of the cancer cell.21 PARP inhibitors are currently being investigated in two Phase II clinical trials and the results are eagerly awaited.

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Conclusion 

In summary, the association of ovarian cancer with inherited BRCA1 and BRCA2 mutations and both ovarian and endometrial cancer with inherited MMR gene mutations have been described for over a decade. Despite identification of germ-line mutations in individuals affected or at high risk of gynaecological cancer, management strategies for these individuals with appropriate risk-reducing surgery or screening is still evolving. However, promising treatments specifically targeting hereditary cancers are being developed and these may open avenues for chemoprevention in the future.

A proportion of familial gynaecological cancer remains unexplained, genome-wide association studies offer hope to identify lower-penetrance genetic variants to explain the excess familial risk.

Practice points

 


•Recognition of inherited cancer syndromes has important implications for patient treatment and for management of the wider family.

•Screening for gynaecological cancers remains of unproven benefit.

•Management of patients with strong family histories of cancer should be performed in conjunction with Clinical Genetics in order to stratify risk appropriately.

•Risk-reducing surgery should be offered to all patients with an inherited predisposition to ovarian cancer, with careful discussion of the advantages and disadvantages.

Research agenda

 


•Targeted individualised treatment strategies for inherited cancer.

•Development of novel screening strategies.

•Counselling women with family histories of cancer but no pathogenic mutation is difficult, therefore further research should focus on identification and evaluation of further genetic susceptibility factors in familial clustering of cancer.

•Future genome-wide association studies may identify low-penetrance genes, which influence susceptibility to gynaecological cancers.

•Individualised risk assessment should be developed for BRCA and MMR gene mutation carriers, incorporating genetic and environmental modifiers.

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PII: S1521-6934(09)00103-5

doi:10.1016/j.bpobgyn.2009.08.002

Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 24, Issue 1 , Pages 3-18, February 2010

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