The Challenge of Cancer Genetics

In the current NEJM there is an interesting article on the heterogeneous nature of cancer cells. Namely in examining renal carcinoma the authors clearly demonstrate the genetic complexity of cancer cells, namely that the cells express a wide variation in genetic changes, the focus being on mTOR.

The authors state:

Multiregion genetic analysis of four consecutive tumors provided evidence of intratumor heterogeneity in every tumor, with spatially separated heterogeneous geneous somatic mutations and chromosomal imbalances leading to phenotypic intratumor diversity (activating mutation in MTOR) and uniformity (loss-of-function mutation in SETD2 and PTEN). Of all somatic mutations found on multiregion  sequencing, 63 to 69% were heterogeneous and thus not detectable in every sequenced region.  Heterogeneous patterns of allelic imbalance were found in all tumors, and ploidy heterogeneity was found in two tumors. Therefore, we found that a single tumor-biopsy specimen reveals a minority of genetic aberrations (including mutations, allelic imbalance, and ploidy) that are present in an entire tumor.

This is a very powerful conclusion. Namely just sampling a single cell is inadequate. Moreover it will become essential to have a dynamic system model which can project the nature of the changes, namely what comes first and then what causes the progression.

The optimism of finding genetic markers which can be used for treatment are made more complex by this somewhat obvious finding. It is obvious from the models of cancer as a complex system, but not obvious from what was known before. That challenge will be to establish models for explaining these changes. The challenge will also be to explain what role the cancer stem cell plays here as well.