NEOPLASTIC DISEASE 



proportion of a population, it is possible to state in general 

 terms what determines the age at which cancer appears. The 

 two significant factors are {a) the frequency with which each 

 of the consecutive mutations needed occurs, and (b) the 

 selective advantage, in the sense of the proportionate in- 

 crease in numbers of the clone concerned, that is provided 

 by each mutation. In individual cases we can be certain that 

 two important additional factors need to be considered, 

 (c) the likeHhood that individual genetic differences will 



• • • \ . • • . X 



• ' . • ' ' ' ' . ** ■ 



* • * • 



* * . * . . . X 



X . • ... 



X • ••'•.•' • . 

 . ' ■ ' ** • * ' ' • 



• X , 



.'^ • .' X . * 

 . • ■ . . " . 



Fig. 12. Graphic comparison of two types of sequential mutation. In ^ 

 no proliferative advantage follows mutation. In B each successive muta- 

 tion confers a proliferative advantage. Successive mutation in cells 

 uniformly present in white background indicated by dot, cross and 

 black square. 



modify the numerical values of {a) and {b), and {d) the in- 

 fluence of traumatic or inflammatory stimuH in increasing 

 the cell turnover and hence providing larger populations 

 subject to mutation and a more rapid opportunity for selec- 

 tive proliferation of mutants. Any mutational step will be 

 significant if it either {a) confers a direct survival advantage 

 on its descendants, or {b) renders the cell line now unduly 

 susceptible to undergo a further mutation which will give 

 such a survival advantage. Mutation on this view will only 

 involve significant change in the cellular constitution of the 

 body if it moves along this fine of increasing prohferative 

 advantage with, as the inevitable end, malignancy. If 



192 



