Principles of major cancer genetics

Hereditary cancer syndromes

Hereditary cancer syndromes arise from germline pathogenic variants in tumour suppressor genes (most commonly) or, less often, oncogenes/DNA repair genes - conferring a substantially elevated lifetime cancer risk compared with the general population and often at a younger age than sporadic cancer
Hereditary cancer accounts for a minority (roughly 5-10%) of most common cancer types overall, but this proportion is much higher in cancers diagnosed at a young age or with a strong family history

The "two-hit" hypothesis (Knudson) explains tumour suppressor gene-driven hereditary cancer: a person inherits one already-mutated copy of the gene (germline), and cancer develops once the second, normal copy is inactivated by a somatic mutation in a single cell - explaining why hereditary cancer syndromes cause earlier-onset, often bilateral/multifocal disease compared with sporadic cancer, which requires two independent somatic hits in the same cell

Red flags for a hereditary cancer syndrome: cancer diagnosed at a young age, multiple affected relatives (especially across generations), bilateral/multifocal disease (e.g. bilateral breast cancer), multiple different primary cancers in one individual, and a cancer type/pattern matching a recognised syndrome (e.g. breast + ovarian for BRCA1/2, colorectal + endometrial for Lynch syndrome)
Formal risk assessment tools and referral criteria (rather than family history alone by impression) more reliably identify who warrants genetic testing

Identified carriers of a hereditary cancer syndrome typically follow enhanced surveillance (earlier/more frequent screening), risk-reducing options (prophylactic surgery in selected high-penetrance syndromes), and cascade testing of relatives
Somatic (tumour-only) genetic testing, distinct from germline testing, is increasingly used to guide targeted cancer therapy selection - a separate question from hereditary risk, though the two are sometimes conflated

BRCA1/2 (breast/ovarian cancer), Lynch syndrome (colorectal/endometrial cancer), Li-Fraumeni syndrome (TP53, multiple cancer types), familial adenomatous polyposis (APC)

Distinguishing germline (hereditary, present in every cell, heritable) from somatic (acquired within the tumour only, not heritable) mutations is fundamental - a mutation found on tumour genomic testing does not necessarily indicate hereditary cancer risk unless separately confirmed on germline testing

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