Mutations in normal breast tissue and breast tumours

The accumulation of mutations is a feature of all normal cells. The probabi lity of any individual gene in any cell acquiring a mutation is, however, l ow. Cancer is therefore a rare disease in comparison with the number of sus ceptible cells. Mutations in normal tissue are stochastic, vary widely amon g cells and are therefore difficult to detect using standard methods becaus e each change is so rare. If, however, a tissue such as the breast undergoe s considerable clonal expansion, particularly if relatively late in life, n ormal tissue may have accumulated many thousands of detectable mutations. S ince breast cancers are clonal and have almost certainly undergone many mor e cell divisions than normal cells, each tumour may have many millions of m utations, most of which are entirely innocent and some of which have accumu lated in the cell of origin prior to tumorigenesis. Despite some claims to the contrary, even at normal mutation rates, clonal expansion within a tumo ur is quite sufficient to account for the mutations of five or six genes th at are generally supposed necessary for carcinogenesis to occur. Hypermutab ility does, however, contribute to the pathogenesis of many cancers and, al though evidence is indirect in breast cancer, may take forms such as karyot ypic instability via centrosome amplification.