VIB–Catholic University Leuven, Belgium

A cancer geneticist looks at the link between small RNA molecules and cancer.

My laboratory studies how cancer cells evade the action of tumour-suppressor (TS) genes. For most TS genes, both copies must be lost to facilitate tumour progression. For some, haploinsufficiency — loss of only one copy — may also contribute to carcinogenesis. However, selection generally favours the inactivation of the remaining functional gene copy to accelerate cancer pathogenesis.

Now, an additional class of haploinsufficient TS genes has been identified. Tyler Jacks at the Massachusetts Institute of Technology in Cambridge and his team found that loss of one copy of the gene Dicer1 enhanced tumour formation in a mouse model of lung cancer, but selection strongly disfavoured loss of both copies (M. S. Kumar et al. Genes Dev. 23, 2700–2704; 2009). Publicly available data reveal that in one-third of human tumours only one copy of DICER1 is deleted.

This finding has several profound implications for cancer mechanisms and therapies. Dicer1 codes for an enzyme involved in the generation of microRNAs, short fragments of RNA that silence specific genes. The study provides mechanistic insight into the long-standing observation that microRNAs are often downregulated in human tumours. Perhaps more importantly, the data strongly indicate that Dicer1 — and, by extension, a subset of microRNAs — are in fact required for tumours to survive and/or grow. Further studies aimed at deciphering the dependency of tumours on Dicer1 or microRNAs should therefore lead to exciting therapeutic possibilities.

Meanwhile, this class of TS genes, for which partial loss is advantageous to tumours but complete loss is disadvantageous, must not be overlooked in the ever-growing number of high-resolution analyses of mutations found in cancer.

University of California, San Francisco, USA

To an epigeneticist, cancer is encrypted in genes and their packaging.

Early in my career I had the good fortune to study epigenetics in a lab focused on the molecular genetics of cancer. At the time, geneticists typically thought that in cancer, epigenetic changes — which affect regulation of the genome but not the genome’s sequence — were epiphenomena less worthy of study.

This might have made the experience akin to being a Republican mayoral candidate in left-leaning San Francisco; instead it was positively transforming.

As my own research group took shape, I began to integrate genetic and epigenetic theories of malignant transformation. Now, hereditary human cancers and genetically engineered mice once held up as evidence for genetic models also provide evidence for epigenetic models, and we study the interactions of the two mechanisms.

In this light, a recent paper (G. G. Wang et al. Nature Cell Biol. 9, 804–812; 2007) captured my attention because it dissects how one genetic change leads to epigenetic changes that ultimately cause leukaemia.

The work focuses on an abnormal fusion protein — produced after part of one gene fused, or translocated, with part of another — and narrows down its cancer-causing properties to a particular region of the protein. This region mediates an epigenetic change: it adds a methyl group to one amino acid of a histone, part of a gene’s packaging in the nucleus.

The team found that the fusion protein misdirects its methylation to the histones that package HoxA genes, triggering further miscoding of the histones. This activates the genes, which promote self-renewal of blood-cell precursors, contributing to leukaemia.

I wonder if the interactions could be traced back even further. Given the role of epigenetics in stabilizing chromosomes; might it have been epigenetic miscoding that made the gene susceptible to translocation in the first place?

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

A geneticist rebuts criticism of cancer genome projects.

What do you learn if you sequence 13,000 genes in 11 breast and 11 colorectal cancer samples? The question taps into an intense debate about how best to identify genes relevant to human cancer.

Last year, researchers reported the results of a survey such as the one described (T. Sjöblom et al. Science 314, 268–274; 2006). They found that each tumour contains, on average, 90 mutant genes — an unexpectedly high number. They also defined mutation spectra that were specific to colon and breast tumours, including the intriguing observation that the DNA letter sequence CG was swapped for GC at high frequency in breast tumours. This could be due to an uncharacterized DNA repair defect or differential carcinogen exposure.

I consider this report a step towards answering key questions in cancer biology, such as how many genes are mutated in cancer, how many mutations are required for cancer, and whether accumulation of genetic alterations in cancer cells drives tumour progression.

But others disagree. Many labs see large-scale sequencing of cancer genomes as unfocused and expensive fishing experiments. I have been doing genomics experiments since the dawn of this era, and have often faced this criticism.

But just this one study has identified more genes mutated in human cancer than thousands of investigators have found over past decades. And another recent, large-scale sequencing project pinpointed close to 120 mutant kinase enzymes that may have a role in human cancers (C. Greenman et al. Nature 446, 153–158; 2007).

Both cases show that the outcome of unbiased, genome-wide studies may not be what we expect, which is exactly why they’re worth doing.