Identification of two potential suppressor gene regions on chromosome arm 14q that are commonly lost in advanced colorectal carcinomas

Background: Remarkably little is known about the molecular alterations cont ributing to the establishment of a distant metastasis from a primary colore ctal carcinoma. Previous studies on primary colorectal carcinomas have sugg ested an association between loss of chromosome 14 sequences and cancer pro gression. Methods: In the present study, we analyzed 20 distant metastases and peripheral blood samples from 18 patients using 24 microsatellite marke rs spanning chromosome arm 14q. In addition, DNA from microdissected corres ponding primary tumors (formalin-fixed and paraffin-embedded) was analyzed at selected 14q loci, Results: Sixty-five percent (13/20) of the metastases , from 11/18 patients, showed loss of one or more markers at 14q, and the m ajority (94%) of the primary carcinomas showed identical 14q genotypes to t hose found in the metastasis, Two minimal common deleted regions were delin eated in the metastases, one between markers D14S288-D14S52 at 14q13-21 and the other between D14S284-D14S81 at 14q24-31, pinpointing two previously u nrecognized map positions for potential target genes. The genotype pattern of five tumors was consistent with monosomy or large chromosomal deletions spanning both potential suppressor regions. The reasons for monosomy in can cer remain unknown, but our data support the hypothesis that deletions of s everal tumor suppressor genes are more readily obtained by one chromosome l oss than by several molecular events, and through this unison loss a growth advantage may be provided. Conclusion: Our data suggest that 14q loss is n ot a rate-limiting event in colorectal metastasis formation, but the high f requency of this alteration in primary tumors with metastatic ability, as w ell as in the metastases themselves, suggests it is part of the tumor clone with selective growth capacity.