Splice-altering mutations and human disease

Researchers report how mutations may contribute to inherited predisposition to cancer by altering RNA splicing. Certain genetic mutations can cause disease by altering splicing of RNA transcripts, but such mutations can be difficult to identify and characterize. Mary-Claire King and colleagues developed a method, called cBROCA, to assess the effects of mutations on RNA splicing. In cBROCA, RNA is isolated from cultured patient lymphoblast cells, reverse-transcribed into complementary DNA, hybridized to a panel of known tumor suppressor genes, and sequenced. Comparison of test and control samples allows identification of altered splicing patterns. The authors applied cBROCA to cancer patients and their relatives from more than 150 families, each having multiple relatives with breast, ovarian, endometrial, or colon cancer, but with negative results from conventional genetic testing. cBROCA analysis identified 120 potential splice-altering mutations in 16 tumor suppressor genes. Mutations were associated with various forms of abnormal splicing, including failure to transcribe part or all of an exon and creation of new exons. In some cases, a single mutation led to multiple altered transcripts. In addition to altering canonical splice sites, mutations could affect splicing through loss or gain of splicing enhancers or silencers. The authors suggest that cBROCA could enhance understanding of the clinical consequences of rare splice-altering mutations.

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Article #19-15608: “Characterization of splice-altering mutations in inherited predisposition to cancer,” by Silvia Casadei et al.

MEDIA CONTACT: Mary-Claire King, University of Washington, Seattle, WA; e-mail:

[email protected]