BLM Mutation and Colorectal Cancer Susceptibility

Abstract

Bloom syndrome (BS) was first described by Dr. David Bloom in 1954 after he observed a small number of patients of Ashkenazi Jewish origin with erythematous lesions of the face and small stature (Bloom 1954). Approximately 10 years later, the chromosomal instability and cancer predisposition of BS were reported (German et al. 1965). BS is a rare autosomal recessive disorder in which affected individuals show preand postnatal growth retardation, sun-sensitive facial erythema, immunodeficiency, and male infertility. Those affected are predisposed to a plethora of cancers, most commonly occurring before the age of 25 (German 1993). Carcinomas are observed with highest frequency, followed by leukemias and lymphomas (German and Ellis 1998). Cytologically, the hallmark of BS is elevated sister chromatid exchange (SCE), approximately 5to 10-fold higher than in cells from unaffected individuals. SCE is often used as a diagnostic marker of BS, although molecular genetic mutational analysis is available. Other cytological features of BS include quadriradial structures, telomere associations, and chromosome breaks (German 1964; German et al. 1965; Chaganti et al. 1974). The disease gene for BS, known as BLM, maps to chromosome 15q26.1 and encodes a 159-kDa protein that is a member of the recQ family of helicases (Ellis et al. 1995). This family of helicases is highly conserved throughout evolution; multicellular organisms have multiple recQ-like helicase genes in contrast to unicellular organisms that have only one. The BLM gene encodes a protein that contains a central helicase domain. Carboxy terminal to the helicase domain is the conserved RQC domain (recQC-terminal) that defines this family of helicases, and the HRDC domain (helicase, RNaseD and C-terminal), a domain common to RNA helicases. A nuclear localization signal is also present in the C terminus of most eukaryotic recQ-like helicases. The human recQ-like helicases have very little Chapter 8.6 BLM Mutation and Colorectal Cancer Susceptibility