Genetic predisposition to cancer

Abstract

-Over recent decades a number of genes causing predisposition to cancer have been identified. Some of these cause rare autosomal dominant monogenic cancer predisposition syndromes. In the majority of families, the increased incidence of cancers is due to a multifactorial aetiology with a number of lower penetrance cancer predisposition genes interacting with environmental factors. Identification of those at increased risk of cancer on account of their family history is important, as genetic testing, enhanced surveillance, prophylactic surgery and chemoprophylaxis may be indicated. In this article the issues surrounding genetic predisposition to cancer are considered by examining two common cancers: colorectal and breast cancer.KEY WORDS: breast, cancer, colorectal, genes, genetic, hereditary, inherited, monogenic, predisposition, surveillanceThe hereditary nature of cancer has been well recognised for over 100 years, but the inherited aspects of cancer susceptibility have become more clearly characterised only in the last few decades. Almost half the referrals to genetics centres are now for assessment of cancer susceptibility compared with only a small minority twenty years ago. Studies of familial aspects of cancer have focused on families with:• several individuals affected with a rare cancer, possibly accompanied by other phenotypic abnormalities • characteristic familial constellations of different cancers, or• an excess of specific 'common cancers' , particularly occurring at young ages.Epidemiological studies have shown that the occurrence of a cancer in one family member confers an increased empirical risk of the same or related cancers to relatives, the degree of risk depending on the age at diagnosis and the number of affected relatives on the same side of the family. Linkage studies in families with several close relatives affected with the same cancer type have led to the identification of the genes underlying a number of monogenic syndromes of cancer predisposition. Some of these are predisposition syndromes which confer susceptibility to cancer alone; in other rare inherited multisystem disorders, cancer predisposition is accompanied by a characteristic phenotype, including facial dysmorphism, neurological pathology or other features.Single gene cancer predisposition syndromes are rare and account for only a small proportion of familial clusters of common cancers. More commonly, familial predisposition may be due to the effects of several less penetrant genes interacting with environmental factors. The search is on for these higher frequency, lower penetrance candidate genes for common cancers. As the members of the orchestra of interacting predisposition and protective genetic factors are characterised, the distinction between inherited and sporadic cancers will become a spectrum rather than dichotomous. The evolution and widespread availability of affordable microarray technology may in the future offer the general population accessible individualised risk profiling for many cancer types...

Familial non-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity

“…A minority of human cancers is recognized as inherited with an autosomal-dominant form of transmission, and the gene responsible for the disease has been characterized (Turnbull & Hodgson 2005). Nevertheless, clustering of a given cancer in the same family is also frequent in those cancers, the majority, that are …”

Aryl Hydrocarbon Receptor Expression Is Associated with a Family History of Upper Gastrointestinal Tract Cancer in a High-Risk Population Exposed to Aromatic Hydrocarbons

“…The observation that a positive family history of cancer is associated with increased cancer risk is well accepted, and it is particularly evident in gastrointestinal, geniturinary, and gynecologic cancers (2-4). This predisposition may be attributable to an inherited genetic susceptibility that, in some instances, is modified by the environment, i.e., a gene-environment interaction (4).…”

“…This predisposition may be attributable to an inherited genetic susceptibility that, in some instances, is modified by the environment, i.e., a gene-environment interaction (4). One such example is the association between tobacco use and specific Cytochrome P450-related enzyme genotypes that predispose the esophagus of smokers to an even higher risk for DNA damage or cancer (37, 38).…”

“…Having a positive family history of cancer is known to be associated with an increased risk for several cancers (2-4). In Linxian, China, a recent prospective study with 15 years of follow-up and over 3,400 incident upper gastrointestinal cancers, including over 1,900 esophageal squamous cell carcinomas, 1000 gastric cardia cancers and 300 gastric noncardia cancers found a positive family history of esophageal or gastric cardia cancer to be significantly associated with increased risk of cancer at all of these sites (5).…”

Dietary advanced lipoxidation products as risk factors for human health – a call for data

“…As pointed out by Kanner, the concentration of ALEs/LPOs could reach micromolar concentrations, possibly exerting profound genotoxic effects. In individuals with certain cancer susceptibility genes [9], mutations might arise that suppress apoptosis, thus favoring clonal expansion and invasion of the cancer cell. Sustained proinflammatory effects by AGE/ALE mediated RAGE activation would be a perfect recipe for enhanced carcinogenesis and metastasis [10].…”