Exonuclease 1 (EXO1) is a candidate gene for
colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to
colorectal cancer in families with phenotypes similar to
hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with
multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple
leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to
colorectal cancer or other HNPCC spectrum
cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for
microsatellite instability (MSI). No individual in these families had developed
colorectal cancer or known colorectal
adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null
tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered
proteins that have
exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple
leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO,
CHML, and OPN3 were also deleted.