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.