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Familial adenomatous polyposis was one of the earliest clinical applications of genetic testing to predict cancer risk and select for invasive screening tests only in those at high cancer risk. APC, a dominantly inherited cancer susceptibility gene (CSG), was recognized clinically many years before it was sequenced in 1993. Finding the specific causative APC mutation in any one family allowed predictive testing to be offered in children to decide which should have colonoscopy screening starting at or just before puberty. Without a gene test all children of an affected parent had to be screened with invasive endoscopies.

Genetic testing means that 50% (on average) of at-risk children can be reassured and do not need screening. A decade after the APC gene was sequenced, mutations in the mismatch repair (MMR) genes MLH1 and MSH2 were identified as the main causes of Lynch syndrome (also known as hereditary non-polyposis colorectal cancer), and mutations in the double-strand DNA break repair genes BRCA1 and BRCA2 as causes of hereditary breast and ovarian cancer. Rapid advances in the speed of DNA sequencing have advanced the pace of gene discovery manyfold. Over 100 genes have now been identified that, when mutated in the inherited genome, substantially increase cancer susceptibility.1 Many of these are very rare and often there is limited knowledge about the absolute cancer risk that any given variant in any one of these rare CSGs may confer.2 It is worth noting that the lifetime penetrance estimates for cancer that are given in initial publications reporting a new cancer susceptibility gene are frequently inflated. Families in which there are many affected cases are often used to discover cancer genes based on affected individuals sharing the same genetic variant. This ascertainment introduces a selection bias that overinflates penetrance estimates. Much bigger studies in many more families are required to get a more balanced picture with narrower confidence estimates of risk. Understanding the implications of genetic susceptibility to cancer in the oncology clinic, at an individual level, a family level and from a societal perspective, is an important, ongoing challenge.

High penetrance cancer predisposition genes

Inheritance of alterations in genes that confer a high lifetime risk of certain malignancies accounts for only approximately 3% of all cancer diagnoses.1 High penetrance cancer predisposition syndromes are important to recognize because of the substantial risks of cancer to individuals usually with younger age at onset of malignancy (Figure 3.1). CSGs with high penetrance account for recognized patterns of associated cancers of different types, including syndromes with very rare tumour types.3

Figure 3.1

Family with typical cancer history due to inherited truncating mutation of BRCA1 gene.

Most hereditary cancer predisposition syndromes are due to the inheritance of a germline mutation in a single copy (allele) of a tumour ...

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