It doesn't always take two

It takes two, so the song goes, and for genes, this is often so. Recessive disorders, for example, require both copies of a gene to be lost. However, some diseases and traits can occur when one wild-type allele is still present. Now, two papers report that a BLM gene mutation — which, when homozygous, causes the recessive, cancer-predisposition disease Bloom syndrome (BS) — surprisingly predisposes mice and humans to intestinal cancer when haploinsufficient. Because BLM is a helicase that maintains genome stability, these papers highlight the crucial role of genome instability in both cancer pathogenesis and predisposition.

Heppner Goss et al. generated a new BS mouse model by targeting the mouse Blm gene with a mutation (Blm^Cin) that causes a premature truncation. This mutation acts as a null allele and simulates a founder mutation (BLM^Ash) that is present in 1% of Ashkenazi Jews.

The authors used two approaches to investigate the effect of Blm haploinsufficiency on tumorigenesis in these mice. First, they injected them with murine leukaemia virus (MLV). Both wild-type and Blm^Cin/+ mice developed metastatic T-cell lymphoma on exposure to this virus, but mutant mice died earlier, despite tumour morphology being the same in both sets of mice. Next, they crossed Blm^Cin/+ mice to Apc^min mice — a mouse model of familial adenomatous polyposis coli. (The min mutant was chosen because the gastrointestinal (GI) tract is where cancer commonly develops in BS patients.) Double heterozygous mutant mice developed twice as many GI adenomas as did Apc^min/Blm^+/+ animals, and many Apc^min/Blm^+/− mice had tumours with high-grade dysplasia. Tumours in both Apc^min/Blm^+/+ and Apc^min/Blm^+/− also showed Apc loss of heterozygosity (LOH). In both mutants, Apc LOH seemed to occur predominantly through the loss of chromosome 18, where Apc is located. However, in some Apc^min/Blm^+/− tumours, Apc loss also occurred through somatic recombination. No neoplasias were seen outside the GI tract, and Blm LOH was not evident in tumour tissue.

The results of Gruber et al. lend further weight to these findings. In a study of 1,244 Ashkenazi Jews with colorectal cancer (CRC), those with CRC were found to be twice as likely to carry the BLM^Ash allele as those Ashkenazi Jews without CRC. These findings, and those of Heppner Goss et al., indicate that BLM haploinsufficiency might compromise the maintenance of genomic integrity, perhaps by causing an increased mutation rate in heterozygous cells, so speeding their progression to tumorigenesis.