To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case–control study of folate intake, related dietary factors and MTHFR polymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12 or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CT v. CC = 0·77 (95 % CI 0·52, 1·16); OR for TT v. CC = 0·62 (95 % CI 0·31, 1·24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0·81 (95 % CI 0·45, 1·49)). There were significant interactions between total folate and C677T (P = 0·029) and A1298C (P = 0·025), and total vitamin B6 and both polymorphisms (C677T, P = 0·016; A1298C, P = 0·033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.
I am very pleased to have been asked to write the Foreword to this important and timely book. As Chair of the Human Genetics Commission I am only too aware of the impact of familial breast cancer, or indeed many other familial cancers, on our work.
The issues raised by an increased understanding of the genetics of breast cancer have formed part of our thinking on how to deal with issues of privacy and confidentiality, such as the provision of genetic information to family members. Moving beyond the clinical, we have also considered some of the issues concerning patenting of gene sequences, taking as one example the continuing debate about the BRCA1 and BRCA2 gene patents. In addition, we have considered familial breast cancer as one of several conditions on the radar of insurance companies before underwriting life or health insurance.
I am therefore pleased to see that a fellow member of the Human Genetics Commission, Professor Patrick Morrison, and his colleagues have so carefully and clearly set out many of these important issues in this book. I hope that it will be widely read by clinicians and those responsible for policy in all of these areas and that they will take note of the important messages herein.
Most countries now have services for familial cancer genetics, but these vary considerably (Harris, 1998; Hodgson et al., 2000). There are, broadly, three potential approaches for developing a clinical service in response to the growing evidence of the links between inherited genetic factors and the risks of developing breast and ovarian cancers:
An ad hoc system of providing advice to patients, i.e. ‘demand led’
The development of a selective system of screening patients who are estimated to be at relatively high genetic risk of developing these cancers
The establishment of systems of population screening to identify patients at increased risk
Over the last few years, many clinics worldwide have been providing advice to patients with a family history of cancer through clinics in an ad hoc and uncoordinated manner, funded largely through ‘soft money’. The resources available have not kept pace with the rapid growth in demand, and this is reflected in the sharp increase in waiting times for appointments in recent years.
Only 5% of breast and ovarian cancers are thought to be due to a strong inherited susceptibility. A process of selection of individuals who are estimated to be at high risk on the basis of their family history for screening for cancer is a more pragmatic approach than screening the general population. However, it is important to demonstrate clearly the benefit of such surveillance programmes before this can be advocated on a large scale (Scottish Office Home and Health Department, 1998).
It is abundantly clear from the contents of this book that our understanding of the inherited aspects of cancer has increased enormously in the past decade. Epidemiological studies (Easton et al., 1995) demonstrate that familial clusters of common cancers could be due to: (1) germline mutations in rare, highly penetrant cancer susceptibility genes, (2) more common, less penetrant mutations, or (3) common environmental factors. It is likely that all of these mechanisms are important. Subsequent to the identification of BRCA1 and BRCA2 (Miki et al., 1994; Wooster et al., 1995), large collaborative studies of families with hereditary breast and ovarian cancer suggest that currently detectable germline mutations in these genes account for approximately 85% of families with six cases of breast cancer but only 41% of those with four to five cases, most families with two ovarian cancer (in addition to breast cancer) cases but 88% (69% due to BRCA1 mutations) with only one ovarian cancer case, while 77% of families with four female cases and one male case of breast cancer are due to BRCA2 and 19% of such families to BRCA1 mutations (Easton et al., 1995; Ford et al., 1998; Thorlacius et al., 1998). Thus a significant proportion of smaller families, particularly those with no cases of ovarian cancer, are likely to be due to polymorphic variants in other genes.
It has long been recognized that some very rare forms of cancer, such as retinoblastoma and neurofibromatosis, are caused by inherited genes. It is only within the last few years, however, that rapid progress has been made in understanding the role that inherited genes also play in determining a proportion of the more common cancers, including breast, colorectal and ovarian cancer. Although there is still uncertainty about the precise contribution of inherited predisposition genes to the incidence of these cancers, the available evidence suggests that breast, colorectal and ovarian cancer have a number of common genetic features.
A small proportion of these cancers (about 5%) are caused by inherited genes which, though comparatively rare, confer very high lifetime risks of developing cancer. In some cases these lifetime risks may be as high as 80%.
Cancers caused by these high penetrance genes are more likely to occur at an early age than sporadic cancers, and 15–20% of the cancers diagnosed in people under the age of 50 years may be accounted for by these genetic mutations.
Carriers of known genetic mutations, which confer high lifetime risks of developing breast or ovarian cancer, are also at significantly increased risk of developing certain other forms of cancer.
A further 10–20% of breast, ovarian and colorectal cancers are likely to be caused by inherited polymorphisms in predisposition genes, which are commoner but less penetrant but which confer some increased risk (more than three times the general population risk).
This publication 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, this book provides the busy clinician with a contemporary and wide-ranging guide to the latest developments in the diagnosis, genetics, screening, prevention and management of familial breast cancer. This area has advanced in knowledge so rapidly that this publication provides an unrivalled source of information including sections on ethical and insurance issues and the different cultural differences in breast cancer. The use of recently devised cancer genetics clinics and different referral criteria and patterns to these clinics are detailed. The volume will be of immense value to all clinical geneticists, oncologists, and healthcare professionals involved in screening and counselling programmes.