Mice Heterozygous for Blm Mutation have Increased Tumor Development

Joanna Groden
University of Cincinnati College of Medicine, and Howard Hughes Medical Institute
P30ES06096

Background: In traditional Mendelian genetics, dominant and recessive genes exist. For example, the gene for blue eyes is recessive while the gene for brown eyes is dominant. If a person inherits one allele for blue eyes from one parent and one for brown from the other parent, he is said to be heterozygous and in this case, since the blue-eyed gene is recessive, he will have brown eyes.

In cancer biology, there are many tumor suppressor and DNA repair genes that are dominant. Therefore, heterozygous animals are sufficiently protected against certain cancers. The gene controlling the formation of Bloom syndrome is a DNA repair gene known as Blm. Bloom syndrome is characterized by small stature, male infertility, a compromised immune system, and increased risk for a variety of tumors including colorectal cancer.

Advance: Researchers at the University of Cincinnati supported jointly by NIEHS, NCI, and the Howard Hughes Medical Institute, report that contrary to the traditional Mendelian inheritance pattern described above, mice heterozygous for Blm are at higher risk for cancer development. When challenged with murine leukemia virus, heterozygous mice developed lymphoma earlier than wild-type mice. Also, when cross matings were performed with mice susceptible to intestinal tumors, heterozygous offspring developed twice the number of intestinal tumors.

Implication: These findings describe the increased risk and genetic mechanism for intestinal cancer development in mice heterozygous for Blm and have implications for cancer risk in humans. In fact, a companion paper published in the same journal describes an epidemiologic study of Ashkenazi Jews which reports that people heterozygous for the same allele were more than twice as likely to develop colorectal cancer as control subjects.

Citations:

• Goss KH, Risinger MA, Kordich JJ, Sanz MM, Straughen JE, Slovek LE, Capobianco AJ, German J, Boivin GP, Groden J. Enhanced tumor formation in mice heterozygous for Blm mutation. Science. 2002 Sep 20;297(5589):2051-3.

• Gruber SB, Ellis NA, Rennert G, Offit K, Scott KK, Almog R, Kolachana P, Bonner JD, Kirchhoff T, Tomsho LP, Nafa K, Pierce H, Low M, Satagopan J, Rennert H, Huang H, Greenson JK, Groden J, Rapaport B, Shia J, Johnson S, Gregersen PK, Harris CC, Boyd J. BLM heterozygosity and the risk of colorectal cancer. Science. 2002 Sep 20;297(5589):2013.

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