“Translational biomedical science” includes relationships between phenomena in different sciences [1]. Historically, a ‘neoplastic process’ was considered the origin of tumours [2], but no gene for the process has been found.

            In tumors, excess growth is most-studied. Little is known of the other individual biological features of tumours such as ‘differentiation’ [3], tendency to invade and metastasise as well as dependence on the kind of parent cell. Particular issues are:

(i) How the biological features occur in the specific combinations seen in the tumour types.

(ii) How variation occurs case-to-case in tumour types (‘inter-case’ variation).

(iii) How variation occurs between different foci in the same case of tumour (‘intra-case’ variation), or in later stages of a tumour (‘progression’).

            This paper suggests

(iv) That the specific combinations of features characterising tumour types indicate ‘linkages’ of phenotypic changes. The combination of features for each tumour type arises by co-mutation of relevant genomic elements in a type-specific complex locus. The elements may not all be protein-coding genes. [4] The abnormalities resulting from each mutant genomic element in the complex locus determines individually, a phenotypic change in the tumour cell. [5]

(v) That case-to-case variation arises because of different functional morphisms in the mutations. [4]

(vi) That intra-case variations, including progressions, occur through genomic instabilities in tumour cell populations.

             The significance of this analysis is that for each tumour type, the ‘critical’ / ‘driver’ mutations’ [6]  may be in a type-specific complex locus of genomic elements, not in one or more non-type-specific genomic elements.

[1] Zerhouni EA. (2005) N Engl J Med., 353(15):1621-3.

[2] Foulds L. (1969, 1976) “Neoplastic Development”, Academic Press, San Diego.

[3] Bignold LP et al. (2007) “David Paul Hansemann: Contributions to Oncology”. Birkhäuser, Basel.

[4] Monteiro AN et al. J Intern Med. (2013) 274(5):414-24.

[5] Bignold LP. (2105) “Principles of Tumors: A Translational Approach to Foundations”, Elsevier / Academic Press, MA.

[6] Raphael BJ et al. (2014) Genome Med.  6(1):5.