Oncology, from empiricism to modern biology (5)

Abstract

The last lecture presented a synthetic view of the genetic complexity of cancer, as it can be understood today thanks to advances in genomics. Drawing on the recent review by B. Vogelstein, I presented the extreme heterogeneity of the number of mutations in the tumor cell genome. Tumors associated with exposure to mutagens (lung, melanoma) have several hundred mutations, while pediatric tumors and certain leukemias sometimes have fewer than five. Only a fraction of these genetic anomalies concern master genes(drivers), those whose anomalies are associated with major biological effects. Of the 150 drivers known to date, only one to six appear to be directly involved in a given tumor. What's more, many of these drivers activate the same proliferation, survival or signalling pathways. The repertoire of regulatory pathways involved in cancer transformation is therefore much smaller than the number of master genes identified to date.

Leukemias are a highly heterogeneous class of diseases. Nevertheless, their genetics are much simpler than those of solid tumors. What's more, the hematopoietic system offers many advantages: cells are easy to harvest and amplify ex vivo. This system has made it possible to answer some key questions, such as the existence of silent mutations in normal stem cells, pre-leukemia mutations in the blood of healthy individuals, or the functional cooperation of these mutations during the transition to leukemia. The discovery of master leukemia abnormalities has been greatly facilitated by the existence of recurrent chromosomal translocations. These translocations lead either to the overexpression of proliferation master genes (such as Myc in Burkitt's lymphoma), or to the formation of fusion genes in myeloid leukemias. These chromosomal anomalies, detected as early as the early 1960s, led to the identification of the first oncogenes in human cancers. More recently, these mutations have been precisely mapped in acute myeloid leukemia. The temporal sequence of these anomalies has been defined, highlighting the central role of early alterations in epigenetic regulators, those responsible for cellular memory and defining hierarchies among progenitors. In some cases, distinct anomalies functionally converge on a single proliferation or survival pathway, as has been demonstrated for the NFkB pathway in lymphomas. High-throughput sequencing techniques have made it possible to demonstrate the Darwinian evolution of a tumor cell population, particularly in response to genotoxic treatments.

Some of the master proteins of transformation may be therapeutic targets, such as BCR/ABL or PML/RARA. In both cases, detailed modeling of the response to treatment has made it possible to determine the cellular mechanisms of remissions and to define a functional hierarchy among leukemia cells. The final part of the lecture outlined the emerging role of p53 in therapeutic response. Recent data on the in vivo functions of this gene were also discussed in the seminar.