Guidelines for risk estimation in individuals with a family history of cancer

Calculation of risk of breast cancer In families where there is no clear-cut Mendelian genetic predisposition, empirical risks for breast cancer may be calculated based on the age at diagnosis of breast Table 11.1. Importance of genetic predisposition to breast cancer Table 11.1. Importance of genetic predisposition to breast cancer Percentage due to genetic susceptibility cancer in first-degree relatives in studies carried out by Houlston et al. (1991) in the UK and by Claus et al. (1996) in...

Clinical pathological and outcome characteristics of BftCArelated ovarian cancer

Clinicopathological characteristics of ovarian tumour have been evaluated in familial aggregation of ovarian cancers or among patients with BRCA1 2 germline mutation (hereditary ovarian cancer). Few data are available for ovarian cancer associated with other inherited genetic syndromes and will not be discussed further here. This whole topic is discussed in detail in Chapter 7. Early age of onset is often considered to be a hallmark of most of the hereditary cancers. As discussed above, in some...

Development of benchmarks for the regional cancer genetics service

Benchmarks can be appropriate indicators of value in monitoring, understanding and predicting what improves the performance of the service. Agreement needs to be reached on what constitutes 'good' and 'poor' quality, and therefore performance, for a given indicator. The services need to be aware of the appropriate comparators, deciding appropriate local regional or national levels against which to compare performance. We have to be very aware of the potential inconsistency or conflict between...

Identification of individuals with a genetic predisposition to cancer

The basic aims of genetic management for breast and ovarian cancer risks are To identify individuals who are at a significantly increased genetic risk of inherited cancer To provide advice and counselling to individuals about their risks of developing cancer To establish evidence-based protocols for the surveillance and management of individuals and families at increased risk, which will reduce morbidity and mortality rate from these diseases To provide patients affected with cancer that is...

Services for cancer genetics

Cancer genetics is a new field and the organization of services in this area may be initiated by clinical genetics services or through oncology and other departments, where individuals with a special interest in cancer genetics arrange to see individuals with a family history of cancer, estimate their cancer risks and arrange surveillance and genetic testing as appropriate. In many parts of Europe, cancer genetics clinics have been established for many years, and most specialized genetic...

Clinical cancer genetic management

The key to proper genetic counselling in CS is recognition of the syndrome. Families with CS should be counselled as for any autosomal dominant trait with high penetrance. What is unclear, however, is the variability of expression between and within families. We suspect that there are CS families who have nothing but trichilemmomas and who, therefore, never come for medical attention. Based on the current data, it might also be prudent to treat all PHTS cases like CS, regardless of their...

Pathology of ovarian cancers in mutation carriers

All studies performed to date indicate that carcinoma is the most common histological diagnosis observed in BRCA1- and BRCA2-associated ovarian cancer. Most of the information available on familial ovarian cancer is based on BRCA1-linked disease because, unlike familial breast cancer patients, BRCA1 germline mutations are approximately four times more common than BRCA2 mutations in ovarian cancer patients (Gayther et al., 1999 Boyd et al., 2000). All five subtypes of malignant epithelial...

Primary care in the cancer genetics service for Wales

Guidelines were drawn up and distributed to all GPs in Wales by the National Assembly for Wales (Box 9.1). Crucially, the guidelines were developed in a multidisciplinary fashion - initially in conjunction with the cancer lead clinicians, public health representatives, voluntary groups, patient groups and GPs. Multiple meetings were required over an 18-month period and all decisions were taken to and endorsed by the Royal College of General Practitioners, the GP committee of the BMA, and the...

Hereditary nonpolyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder associated with germline mutations in five mismatch repair genes MSH2, MLH1, PMS1, PMS2 and MSH6 (Lynch and de la Chapelle, 1999). The protein products of HNPCC genes are key players in the correction of mismatches that arise during DNA replication. Mismatch repair (MMR) deficiency gives rise to microsatellite instability (MSI). MSI results from repetitive non-coding DNA sequences of unknown function found...

Familial Breast Ovarian Cancer

Hodgson and Neva E. Haites more information - www.cambridge.org 9780521803731 This book surveys the profound and far-reaching ramifications that have arisen from the very significant advances in our understanding of the genetic basis of familial breast and ovarian cancer. Written by international experts from Europe and North America, it provides the busy clinician with a contemporary and wide-ranging guide to the latest developments in the diagnosis, genetics,...

Familial ovarian cancer

Ovarian cancer is the fifth most common cancer in women (excluding skin) in the USA and UK. Since the prognosis of this neoplasm is largely determined by the stage of the disease at presentation, and approximately 80 of cases have spread beyond the ovary when first diagnosed, ovarian cancer accounts for a disproportionate number of deaths compared with other cancers of the female genital tract. A family history of ovarian cancer confers the highest known risk factor for developing the disease....

Population versus highrisk group screening

Population screening in women over 50 years of age, with mammography every second year, is beneficial, although cost-effectiveness is debated. The merit of such Figure 13.2 Annual incidence rate for breast and or ovarian cancer for BRCA1 mutation carriers. Figure 13.2 Annual incidence rate for breast and or ovarian cancer for BRCA1 mutation carriers. screening before 50 years of age is controversial. Looking more closely at the effect of screening over the age of 50, the benefit seems to...

Different basis for risk prediction

Without consideration of family history or other risk factors, lifetime risk for breast cancer for an individual can be estimated by using the cumulative risk of breast cancer in the general population, which varies considerably between countries. It is 10 in the UK female population or approximately 1 in 10. The longer a woman lives without cancer, the lower is her risk of developing breast cancer in the remainder of her lifetime. Menstrual and reproductive history, such as early age at...

Genetic testing

Mutation searches and predictive testing Before an individual who has not had cancer can be tested to determine whether or not they have inherited a susceptibility to breast or ovarian cancer, it is first necessary to undertake a germline mutation test. This involves taking a blood sample from a member of the family who has had breast or ovarian cancer and where there is a high chance of a genetic mutation. The BRCA1 and BRCA2 genes are then analysed to determine whether a mutation exists. If a...

Low penetrancemodifier genes

Candidate genes with a function known to be consistent with a potential role in carcinogenesis have been studied to determine whether they influence the risk of breast cancer in both the general population and, more recently, in individuals carrying BRCA1 and BRCA2 gene mutations. The polymorphisms in these genes are usually common in the general population and may be associated with a small increased risk. They may only be seen to have an effect in carriers of other known gene mutations or in...

Perspectives and conclusion

Predictive genetics in oncology opens considerable perspectives in diagnostic and therapeutic approaches of cancer. Multiples issues still exist in the hereditary breast ovarian cancer syndrome (Kuerer et al., 2000), but the perspective of preventive and screening procedures being potentially effective is very encouraging. Current recommendations for the management of BRCA1 2 mutation carriers are mostly based on inferences and expert opinions and not on data from randomized controlled trials....

Prophylaxis

Some patients with familial ovarian cancer syndromes have a lifetime cumulative risk of developing ovarian cancer of 60-70 . In these situations, a prophylactic bilateral oophorectomy is warranted. Prophylactic oophorectomy is divided into primary prophylactic surgery, where apparently normal ovaries are removed, and secondary prophylactic surgery, where ovaries are removed at surgery for a benign condition. The main dilemma lies in the correct timing of the procedure, how the procedure is...

Molecular pathology of BRCAl2associated breast cancers

Since its discovery in 1960, oestrogen receptor (ER) has become an important prognostic and predictive marker for breast cancer (Osborne, 1998). ER expression is inversely correlated with tumour grade (Henderson and Patek, 1998) hence, BRCA-associated tumours, which are more often of a higher grade than those of sporadic breast cancer, would be predicted to be more often ER-negative. Many studies have shown low levels of ER expression in familial breast cancers (Johannsson et al., 1997 Osin et...

Pathology of breast cancers in mutation carriers

There are a number of published studies indicating that breast cancers arising in mutation carriers are of higher grade than sporadic cancers (Bignon et al., 1995 Jacquemier et al., 1995 Eisinger et al., 1996 Marcus et al., 1996). Eisenger et al. studied 27 BRCA1-associated breast cancers from 14 families and compared these to sporadic breast cancers, matching for grade. They found an excess of grade III carcinomas in the BRCA1-associated group. Marcus et al. reported the first large series of...

Do ovarian and breast cancer belong to the tumour spectrum of HNPCC

Watson and Lynch (1993) evaluated the frequency of cancer in 1300 high-risk members of 23 extended kindreds with HNPCC. They reported 13 cases of ovarian cancers (mean age at diagnosis 40 years) in these families, while 3.6 were expected on the basis of the general population incidence (observed expected ratio 3.5, P < 0.001 ). Vasen compared the risk of developing ovarian cancer between carriers of an MLH1 mutation (n 124) and carriers of an MSH2 mutation (n 86) (Vasen et al., 1996). He...

Studies of familial breast cancer

It has been recognized for many years that there is an association in certain families between breast and ovarian cancer. The risk for epithelial ovarian cancer was found to be significantly elevated in patients with first-degree relatives affected with breast cancer (twice the population risk) (Muderspach, 1994 Claus et al., 1996). Similarly, the risk for breast cancer was found to be elevated in patients who had first-degree relatives with ovarian cancer. Following international studies of...

Genes implicated in breast cancer predisposition

The BRCA1 gene on chromosome 17q21 was identified by positional cloning methods and found to have 5592 coding nucleotides that are distributed over 100 000 bases of genomic DNA and has 22 coding exons. These encode a protein of 1863 amino acids. Loss of the wild-type allele was found in over 90 of tumours from women with a germline mutation in BRCA1, and hence it is regarded as a tumour suppressor gene. In addition, transfection of wild-type BRCA1 into breast ovarian cell lines decreased cell...

Grading and staging of familial ovarian cancers

The first report on BRCA1-associated ovarian carcinoma found that, overall, the tumours were of higher grade and higher stage than their historic age-matched controls (Rubin et al., 1996). However, grade I stage I tumours have been observed, suggesting that loss of differentiation occurs in parallel with spread of disease. These findings have been largely reproduced by a number of other groups (Aida et al., 1998). Werness et al. (2000a) and Boyd et al. (2000) also found fewer low-grade...

Genetic analysis mutation screening

Screening for mutation in the two highly penetrant breast cancer susceptibility genes, BRCA1 and BRCA2, in affected family members is the preferred method for obtaining a more accurate risk estimate for unaffected women in high-risk families. The identification of a functionally relevant mutation in an affected woman will permit differentiation between gene carrier and non-gene carrier status in family members tested for the identified mutation and thus more accurate quantification of risk for...

Breast and ovarian cancer in other hereditary colorectal cancer syndromes

Cancer of the breast and ovaries has also been observed in two hereditary colorectal cancer syndromes associated with hamartomatous polyposis, i.e. the Peutz-Jeghers syndrome and Cowden syndrome. Peutz-Jeghers (PJ) syndrome is characterized by hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa and lips (Vasen, 2000). The syndrome is caused by germline mutations in STK11 LKB1, a serine-threonine kinase located on chromosome 19. The PJ syndrome is associated with...

Family history as an indicator of predisposition to breast cancer

A history of breast cancer among relatives has been found, in epidemiological studies, to be an indication of breast cancer risk. Familial breast cancer is characterized by a younger age at diagnosis than sporadic forms, increasing numbers of affected family members, an increased risk of bilateral breast cancer, and a strong association with ovarian cancer. Table 2.1. Genetic syndromes associated with breast cancer susceptibility Table 2.1. Genetic syndromes associated with breast cancer...

Cryptic PHTS

Because the spectrum of PHTS may be broader than was previously believed, it would be important to recognize cryptic cases. Since CS, in and of itself, is difficult to diagnose clinically, PTEN mutation frequencies in series of 'CS' individuals ranged from a low of 10 (Tsou et al., 1997) to a high of 81 (Marsh et al., 1998b). The highest mutation frequencies are obtained when CS is strictly defined by the operational diagnostic criteria of the International Cowden syndrome Consortium (Table...

Pedigree analysis

For genetic counselling of women with a family history of breast cancer, the commonly employed model for estimating breast cancer risk is based on the Cancer and Steroid Hormone (CASH) study - a large population-based, case-control study of breast cancer comprising 4730 patients diagnosed at 20-54 years and 4688 control subjects. The Claus model is based on a genetic model of rare highly penetrant genes for susceptibility to breast cancer and therefore includes more information about family...

Conclusion On Ovarian Cancer

Patients who come from FOC families who have established ovarian cancer should be managed in the same way as those from sporadic ovarian cancer families. It may be that, with time, subtle biological differences will emerge. For the asymptomatic patient there are some very difficult decisions to make, particularly as regards genetic testing and prophylactic oophorectomy. The results of screening trials will hopefully go some way to help in making these decisions informed decisions. Advanced...

Is the calculated carrier probability valid for the prediction of mutations

In most countries, a woman has to have a certain level of risk before testing for mutations in the BRCA genes is considered. Women from low-risk families rarely test positive due to the low prevalence of BRCA mutations in the population (Peto et al., 1999 Hopper et al., 1999) thus a negative test will not provide important information about the breast cancer risk. Some of the indications for carrying a BRCA mutation are multiple early-onset breast cancer (under 50 years) in the family, ovarian...

Studies of gene therapy for breast and ovarian cancer

Over the past 10 years there has been a large amount of research into gene therapy for ovarian and breast cancer. It is important to appreciate that many of these studies have only been involved in cell culture or animal models and have yet to be studied in human subjects. Others have proven initially successful in pre-clinical models but have failed to show a benefit in the treatment of humans. Unfortu nately, as many of the clinical studies have been disappointing, the results are often only...

Cowden syndrome

CS usually presents by the late twenties. It is believed that more than 90 of affected individuals manifest a phenotype by their twenties (Nelen et al., 1996 Eng, 2000b). By the third decade, 99 of affected individuals would have developed the mucocutaneous stigmata, although any of the features could be present already (Tables 3.1 and 3.2). Because the clinical literature on CS consists mostly of reports of the most obvious or most unusual families, or case reports by sub-specialists...

Conclusion Of Ovarain Cancer

The rapidly evolving practice of clinical genetics is throwing up many questions to which we do not yet have clear answers. This is nowhere more apparent than in the genetics of common cancers, including breast cancer, which is the fastest growing area of genetic medicine. If this chapter has dwelt on problems rather than solutions, this is a reflection of the current 'state of the art' rather than of any underlying pessimism. We live in exciting and, above all, hopeful times. Given the pace of...

Conclusions

Ovarian cancer most commonly presents as advanced-stage disease with a poor prognosis. In the absence of a known pre-malignant lesion, the ability to detect early-stage disease is clearly desirable. However, as yet, no conclusive evidence is available to prove that screening has an impact on ovarian cancer mortality. The adoption of annual screening as standard practice in the high-risk population makes it impossible to institute a randomized control trial with a control group who are not...

Ipsi and contralateral breast cancer recurrences

Lumpectomy followed by radiation therapy, i.e. the conservative management of breast cancer, has been accepted as a standard of care for the majority of women with early breast cancer. Long-term follow-up data have consistently shown a risk of ipsilateral breast tumour recurrence IBTR of 0.5-2 per year Recht et al., 1988 Fourquet et al., 1989 Kurtz et al., 1989 Fisher et al., 1991 Veronesi et al., 1995 , but breast cancer survival was not significantly affected by IBTR when compared with...

Acknowledgements

This chapter is based in part on two previously published works of the authors 'Hereditary ovarian cancer' by Kasprzak et al. 1999 and 'Risk assessment and genetic testing' by Chappuis and Foulkes 2002 . POC is funded by grants from the Ligue Genevoise contre le Cancer et Cancer et Solidarite Fondation, Geneva, Switzerland. WDF is a Boursier Chercheur Clinicien J2 of the Fonds de la Recherche en Sante du Quebec. Abeliovich D, Kaduri L, Lerer I, et al. 1997 . The founder mutations 185delAG and...