Inherited cancer risk
This page presents information on high-risk mutations and familial cancer syndromes , and low-risk genetic polymorphisms.
The majority of cancers are sporadic. They are caused by the progressive accumulation of genetic mutations and/or epigenetic changes during a person's lifetime. These are known as somatic mutations – they affect a particular tissue and are not heritable.
Certain inherited, natural variations in our genes (known as polymorphisms) may also influence the risk of developing a sporadic cancer.
In contrast, some individuals are born with a markedly increased susceptibility to cancer. The inheritance of a single genetic mutation may be sufficient to greatly increase the susceptibility to one or more types of cancer, and this susceptibility can be passed from generation to generation.
The inheritance of these mutations results in families in which a number of individuals develop a certain type(s) of cancer. These are generally referred to as inherited cancers.
High-risk mutations and familial cancer syndromes
Some cases of cancer are caused by the inheritance of a high-risk mutation in a particular gene. It is estimated that around one per cent of all cancers are caused by these high-risk mutations, which generally affect tumour suppressor genes.
However, germ-line mutations in proto-oncogenes do rarely occur, for example, mutations in RET and MET proto-oncogenes cause multiple endocrine neoplasia type 2 and familial papillary renal cell carcinoma, respectively.1,2
People who carry a high-risk tumour suppressor gene mutation have, on average, a one in two chance of passing the faulty gene on to their offspring. The mutation is passed on through the egg or sperm and is copied to every cell in the child’s body.
Unless both parents are carriers, the child inherits one mutated and one normal allele of the affected gene. This increases their predisposition to cancer, since, even if both alleles need to be mutated in order for a cancer to develop, these individuals only require one more mutation to occur in order to lose the function of that gene. This explains why cancers often arise at a much earlier age in these individuals compared to the general population.
Some high-risk susceptibility genes are associated with very rare familial cancer syndromes (Table 3.1). These are usually characterised by a range of cancers occurring at different, often unusual, sites. Despite the rarity of these syndromes, the large numbers of cases in some affected families have helped in identifying the faulty genes involved.
Other high-risk, inherited mutations have been identified that predispose to some of the more common cancers, including breast, ovarian and bowel cancer (Table 3.2). People carrying these mutations are at high risk of developing the associated cancer(s), but overall the mutations are responsible for only a small proportion of all cases of the cancer.
For example, inherited faults in the high-risk breast cancer genes BRCA1 and BRCA2 account for most familial cases where four or more members of the family are affected by breast cancer, but only for 2–5 per cent of breast cancer cases overall.3
Faults in BRCA1, and to a lesser extent BRCA2, are also associated with an increased risk of ovarian cancer. They account for 80 per cent and 14 per cent, respectively, of families with both ovarian cancer and four or more cases of breast cancer.
BRCA2 mutations also predispose to breast cancer in men as well as in women. Around three-quarters of families with cases of both male and female breast cancer carry mutations in BRCA2. Faults in BRCA1 and BRCA2 are also associated with increased risks of prostate, bowel and pancreatic cancers (Table 3.2).
Two well-known familial bowel cancer syndromes are caused by high-risk mutations in known genes.
Familial adenomatous polyposis (FAP) is caused by a fault in the APC gene, and is characterised by the growth of thousands of intestinal polyps, one or more of which is likely to become cancerous. But FAP accounts for less than one per cent of all colorectal cancers.
Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is more common. It is caused by a fault in one of a family of DNA repair genes, called mismatch repair genes. Mutations in either of the genes MLH1 and MSH2, account for up to 90 per cent of familial cases.
Faults in mismatch repair genes are found in only three per cent of all bowel cancer patients, but when present, confer a lifetime risk of bowel cancer in men of up to 80 per cent (the risk for women is thought to be lower), as well as an increased risk of stomach cancer. Women also have increased risks of uterine cancer (lifetime risk of 60 per cent) and ovarian cancer (lifetime risk of 12 per cent).4
Both FAP and HNPCC are caused by the inheritance of one mutated allele of the associated genes, in an autosomal dominant manner. However, a more recently discovered bowel cancer syndrome, MYH polyposis, is autosomal recessive – both alleles of the MYH gene (also known as MUTYH) need to be mutated in order for an individual to be affected.5
Clinically, MYH polyposis resembles FAP, but the majority of affected individuals tend to have less than 100 polyps, compared to the many thousands seen in individuals with FAP.
Low-risk genetic polymorphisms
The tendency of cancers to aggregate in families cannot be wholly explained by rare, high-risk, inherited mutations. A substantial proportion of such cancers are thought to be attributable to the combined effects of multiple, common gene variants, known as polymorphisms, each of which is associated with a small increase in cancer risk.6
A number of polymorphisms that affect the risk of developing different types of cancer have already been identified.7 But there are likely to be many more and discovering them is the focus of intensive research. This search is being facilitated by the availability of the human genome sequence and the development of high-throughput single nucleotide polymorphism (SNP) array technology 8 (Figure 3.1).
Mutations in BRCA1 and BRCA2 do not account for all familial breast cancers. While it is possible that high-risk mutations in other breast cancer genes have yet to be discovered, this is considered unlikely. It is more likely that most cases are due to families carrying one or more genetic polymorphisms.
A study of a variant of the CHEK2 gene, called 1100delC, indicates that inheriting this polymorphism doubles a woman's risk of breast cancer, and increases the risk of male breast cancer by ten-fold.9 Analysis of the risk of breast cancer in the families of women with bilateral breast cancer indicates that this CHEK2 variant interacts with other polymorphisms to contribute towards the development of the disease.10
The first ever large-scale whole genome search to identify genetic variations that influence risk of breast cancer has recently been completed.11 The study identified five new susceptibility loci for the disease, and suggested genes at these loci that may be involved in breast cancer.
Another recent, similar study has identified a common polymorphism that is associated with bowel cancer.12
Polymorphisms are also thought to play an important role in testicular cancer. Brothers of men with testicular cancer have an eight to ten-fold increased risk of the disease, amongst the highest relative familial risk of any cancer. Fathers and sons of men with testicular cancer have a four to six-fold increase in risk.
Recent genetic studies suggest that a number of polymorphisms, each with a relatively weak effect, are involved in the disease. Work is ongoing to identify these polymorphisms, using technologies such as SNP genotyping13(Figure 3.1).
Irrespective of family history, an individual’s risk of developing cancer is likely to be influenced by their genetic make-up, most commonly by the combination of polymorphisms that they have inherited. The interaction of these gene variants with each other and with environmental risk factors, such as lifestyle factors, is likely to determine overall cancer risk.
Candidate genes in which polymorphisms may affect cancer risk include those involved in carcinogen metabolism (for example, CYP1A1, CYP1A2), DNA repair (for example, ATM) and hormone activity (for example, the androgen receptor gene).336 Identifying these polymorphisms will almost certainly lead to a much better understanding of differences in susceptibility to environmental and lifestyle risk factors, and raises the intriguing possibility of tailoring cancer prevention strategies to an individual's genetic make-up.
It should also help explain variations in cancer risk between populations. It is likely that some of these polymorphisms also influence a person’s response to cancer treatment. This could therefore contribute to the exciting prospect of using 'genetic profiling' to determine the most appropriate treatment for each patient.
References
- Mulligan, L.M., et al., Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature, 1993. 363(6428): p. 458-60
- Schmidt, L., et al., Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet, 1997. 16(1): p. 68-73
- Ford, D., et al., Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet, 1998. 62(3): p. 676-89.
- Aarnio, M., et al., Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer, 1999. 81: p. 214-218
- Jo, W.S. and D.C. Chung, Genetics of hereditary colorectal cancer. Semin Oncol, 2005. 32(1): p. 11-23
- Peto, J. and R.S. Houlston, Genetics and the common cancers. Eur J Cancer, 2001. 37 Suppl 8: p. S88-96
- Houlston, R.S. and J. Peto, The search for low-penetrance cancer susceptibility alleles. Oncogene, 2004. 23(38): p. 6471-6
- Engle, L.J., C.L. Simpson, and J.E. Landers, Using high-throughput SNP technologies to study cancer. Oncogene, 2006. 25(11): p. 1594-601
- Meijers-Heijboer, H., et al., Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet, 2002. 31(1): p. 55-9.
- Johnson, N., et al., Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. Lancet, 2005. 366(9496): p. 1554-7
- Easton, D.F., et al., Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 2007. 447(7148): p. 1087-93
- Tomlinson, I., et al., A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet, 2007. 39(8): p. 984-8
- Crockford, G.P., et al., Genome-wide linkage screen for testicular germ cell tumour susceptibility loci. Hum Mol Genet, 2006. 15(3): p. 443-51
- Lutke Holzik, M.F., et al., Re-analysis of the Xq27-Xq28 region suggests a weak association of an X-linked gene with sporadic testicular germ cell tumour without cryptorchidism. Eur J Cancer, 2006. 42(12): p. 1869-74
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