Reduced Fhit expression in sporadic and BRCA2-linked breast carcinomas

Evidence for alteration of the FHIT gene in a significant fraction of breas t carcinomas has been reported, in apparent concordance with loss of hetero zygosity (LOH) at chromosome region 3p14.2 in breast cancer and benign prol iferative breast disease, A significantly higher frequency of LOH at the FH IT locus was reported for BRCA2(-/-) tumors, possibly due to misrepaired do uble-strand breaks at this common fragile region, To determine whether such genomic alterations lead to Fhit inactivation, we have assessed the level of Fhit expression by immunohistochemical detection in sporadic tumors and cancers occurring in BRCA2 999del5 carriers. To determine whether Fhit inac tivation may have prognostic significance, we have also assessed expression of breast cancer markers and clinical features in sporadic tumors relative to Fhit expression. Of 40 consecutive sporadic breast carcinomas studied f or tumor markers, 50% showed reduced Fhit expression; In these sporadic can cers, loss of Fhit expression was not correlated significantly with the pre sence or absence of other tumor markers. In a study of 58 sporadic and 34 B RCA2 999del5 Icelandic invasive cancers, there was a significant associatio n of LOH at 3p14.2 with reduced expression of Fhit (P = 0.001); also the lo wer expression of Fhit and higher LOB at 3p14.2 in BRCA2 999del5 tumors rel ative to sporadic cancers was significant (P = 0.002), Thus, genetic altera tion at the fragile site within the FHIT gene leads to loss of Fhit protein in a significant fraction of sporadic breast cancers and a much larger fra ction of familial breast cancers with an inherited BRCA2 mutation, consiste nt with the Idea that loss of BRCA2 function affects stability of the FHIT/ FRA3B locus.