Thursday, May 31, 2007

About 90 percent of CLL is sporadic, a germline mutation in gene for a micro RNA was discovered in 2005


Researchers have discovered the first inherited gene mutation that increases a person's risk for chronic lymphocytic leukemia (CLL), one of the most common forms of the disease.

The study shows that the inherited mutation greatly reduces the gene's protective activity. Furthermore, a second kind of change occurs later that turns the gene off altogether, leading to leukemia. This latter alteration is a chemical change that is not inherited.

The findings could help identify people at risk for chronic leukemia, but they also may provide new insights into the process of natural cell death. They may even lead to new strategies for treating the disease.

The research is to be published in the June 1 issue of the journal Cell. It was led by researchers at the Ohio State University Comprehensive Cancer Center

About 90 percent of CLL cases are sporadic; that is, they have no genetic component.

But about one in 10 people with CLL have relatives who also develop the disease – strong evidence of a hereditary predisposition. However, usually only two or three people within a family are affected, making it difficult to do the genetic studies needed to find possible mutations, Plass says.

The family examined in this research was identified by collaborator Henry Lynch at Creighton University.

The researchers are now studying the chemical pathway that regulates the gene, considering possible therapies, working to identify other CLL families and looking for other predisposing genes.

In 2005, other Ohio State Comprehensive Cancer Center researchers discovered a germline mutation in a gene for a microRNA that is implicated in CLL, suggesting that this may also be a predisposing mutation for the disease. -Ohio State University


1: N Engl J Med. 2005 Oct 27;353(17):1793-801. Links
Erratum in:
N Engl J Med. 2006 Aug 3;355(5):533.
Comment in:
N Engl J Med. 2005 Oct 27;353(17):1768-71.
N Engl J Med. 2006 Feb 2;354(5):524-5; author reply 524-5.
N Engl J Med. 2006 Feb 2;354(5):524-5; author reply 524-5.
A MicroRNA signature associated with prognosis and progression in chronic
lymphocytic leukemia.Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM.
Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.

BACKGROUND: MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL. METHODS: We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities. RESULTS: A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P<0.001). CONCLUSIONS: A unique microRNA signature is associated with prognostic factors and disease progression in CLL. Mutations in microRNA transcripts are common and may have functional importance. Copyright 2005 Massachusetts Medical Society.

PMID: 16251535 [PubMed - indexed for MEDLINE

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