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

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...

Contributors

Department of Surgery, Withington Hospital, Manchester, UK University of Heidelberg, Department of Tropical Hygiene and Public Health, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany Psychosocial Oncology Group, Cancer Research UK, London, UK Gynaecological Oncology Unit, St Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, UK Department of Medical Genetics, St Mary's Hospital, Manchester, UK Division of Epidemiology, German Cancer Research...

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...

Familial ovarian cancer

Familial aggregation of ovarian cancer has been variably defined as occurring when 1 two first-degree relatives have ovarian cancer, or 2 the proband has ovarian cancer as well as one or more of her first- or second-degree relatives Lynch and Lynch, 1992 . Case-control studies designed to estimate the relative risk of developing ovarian cancer associated with a family history of the disease are summarized in Table 4.1. In a meta-analysis of case-control and cohort studies on family history and...

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...

Differential diagnosis

CS has variable expression, and thus, this disorder may be considered as a great imitator of many syndromes. BRR could be considered in the differential diagnosis although, with the identification of PTEN mutations in this syndrome, most believe that CS and at least a subset of BRR should be considered as a single genetic entity with the proposed name of 'PTEN Hamartoma Tumour Syndrome' or 'PHTS' Marsh et al., 1999 . The PHTS entity is particularly germane because there are currently more than...

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...