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...

Recent data from the Dutch HNPCC registry

Currently, almost 200 families suspected of HNPCC are known at the Dutch registry, 138 of which meet the Amsterdam criteria or harbour an MMR gene germline mutation. In 79 families, a germline mutation has been detected 34 mutations in MLH1, 40 in MSH2 and 5 in MSH6. In these families, 24 cases of ovarian cancer were observed 6 in families associated with an MLH1 mutation, 13 in families with an MSH2 mutation, none in the families with an MSH6 mutation, and 5 in the families without an...

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...

Should the management of familial ovarian cancer differ from that of sporadic ovarian cancer

The management of familial ovarian cancer (FOC) is currently essentially the same as for sporadic ovarian cancer, but is FOC biologically different from sporadic ovarian cancer and should we be managing it differently There is some conflicting evidence. Greggi examined eight families with two or more first-degree relatives affected with epithelial ovarian cancer (EOC) among a series of 138 consecutive ovarian cancer patients. No significant difference was detected in clinical and pathological...

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....

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...

Cancer genetics services

A survey of cancer genetics services, particularly in relation to breast cancer, in 34 European countries was undertaken as part of a BIOMED II Demonstration Project - 'Familial Breast Cancer, an Audit of a New Development in Medical Practice in European Countries' - and the results have been published in detail (Hodgson et al., 1999, 2000). There was considerable variation between the current status of such services in the different countries. The UK, the Netherlands, Belgium and the...

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...

Breast cancer

In the scheme proposed for managing varying levels of genetic risk, guidelines might be aimed at the primary care team to ensure that the GP can be confident in reassuring low-risk women (de Bock et al., 1999 Evans and Eccles, 2000). In the hospital-based screening clinic, guidelines and a working knowledge of the relevant literature should allow both patient and clinician to feel confident that a more thorough review of the family tree can help inform a more detailed assessment of risk (The...

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...

Founder effects involving BRCA1 and BRCA2

Specific BRCA1 2 mutations are highly prevalent in population subgroups, such as those identified among Jewish women of central European (Ashkenazi) origin. Approximately 10 of mutations in BRCA1 (Struewing et al., 1997 Bar-Sade et al., 1998 Fodor et al., 1998) found in cases of breast cancer are accounted for by 185delAG and 5382insC mutations. With the BRCA2 mutation, 6174delT, these three mutations together may account for a quarter of all cases of early-onset breast cancer and two-thirds of...

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...

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...

Somatic PTEN alterations in sporadic tumours

It is not uncommon to find a high frequency of somatic mutations in a gene, X, in sporadic counterpart tumours that are components of an inherited cancer syndrome whose susceptibility gene is X. For example, germline mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2, which is characterized by medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (reviewed by Eng, 2000a). Somatic RET mutations have been found in 20-80 of sporadic medullary thyroid...

Clinical pathological and outcome characteristics of BRCArelated 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...

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...

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...

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...

Conclusion

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...

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...

Introduction

Breast cancer is the most common cancer in women, accounting for 20 of all new cases of cancer. The lifetime risk to a woman in the UK is 1 in 12 females, with an incidence of less than 10 per 100 000 women aged under 30 years, rising to 300 per 100 000 in women aged over 85 years. Breast cancer can occur in sporadic and hereditary forms, and both forms are associated with modification to the genetic material. In the case of hereditary forms, a constitutive mutation in a specific gene...

Heterogeneity

As can be seen in Table 2.3, Ford et al. carried out heterogeneity analyses using BRCA1 2 linkage data. With the Cancer and Steroid Hormone (CASH) model being assumed for all genes, they estimated the proportions of families linked to each gene depending on the family structure and prevalence of cancer. This suggested that 52 of breast cancer in families was due to BRCA1 and 35 to BRCA2. They also estimated the proportions under the assumption that BRCA1 confers the risks estimated in previous...

Genetic testing

The decision as to whether or not genetic testing should be carried out in individual cases does not lie solely with the responsible clinician. The final decision must rest upon the informed consent of the individual. This means that patients must receive sufficient information, in a way that they can understand, concerning the proposed management, the possible alternatives and any risks. The information must be given in a non-directive manner, so that they themselves can make a balanced...

Confidentiality of family medical history

A recurring theme in clinical genetics is the difficulty of balancing an individual's right to privacy against the duty to share relevant information with the wider family. The enormous increase in the potential for genetic analysis in recent years has raised public awareness of the risks of 'genetic discrimination' in education, employment, insurance and access to health care. These are genuine concerns that society must address but the initial reaction, which is often to propose legislation...

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...

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...

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,...