Lossofheterozygosity ontheshort armofchromosome 17is associated withhighproliferative capacity andDNA aneuploidy inprimary humanbreast cancer

Lossofheterozygosity (LOH)ontheshort armofchromosome 17(17p) wasfoundin27of52(52%) previously untreated primary breast cancers. Therewasa significant correlation between this 17pallelic loss andtwo parameters associated withaggressive tumorbehavior: high cellular proliferative fraction andDNA aneuploidy. These correlations withhighcellular proliferative fraction andDNA aneuploidy werenotfound intumors withLOHatnineother chromosome locations. Thep53gene, aputative tumorsup- pressor genelocated at17p13, wasexamined foraberrations to determine whether itisthetarget forthe17pLOHinbreast cancer. Unlike other types ofhumancancer, there wereno homozygous deletions orrearrangements ofthep53gene, and only 2of13(15%) weremutated intheconserved region where mutational "hotspots" havebeenpreviously located. There- fore, wehypothesize that, inbreast cancer, either loss or inactivation ofgene(s) onchromosome 17pother thanthep53 geneoradifferent mechanism ofp53geneinactivation maybe responsible fortheobserved highlabeling index andDNA aneuploidy associated withLOH at17p. Lossofheterozygosity (LOH)atchromosomal locations associated withtumorsuppressor geneshasrecently been implicated inthegenesis ofmanyforms ofhumanmalignan- cies (1,2).LOH atchromosome 17phasbeenreported in various humancancers, including colorectal carcinomas (3), lungcancers (4), andglioblastomas (5), andinneurofibro- matosis (6). Inbreast cancers, 50-60%ofcases haveallelic losses atthis region (7-10). Todate, correlations havenot beenreported between LOHat17pandvarious clinicopatho- logical parameters ofbreast cancers, including nodal status, presence ofhormone receptors, tumorstage, andhistology (9, 10). Thep53gene, a53-kDa nuclear phosphoprotein (11), has beenassigned tochromosome region 17p13 (12). Several studies haveindicated thatthewild-type p53geneproduct functions asatumorsuppressor (13,14). Inexperimental systems aswellasinhumantumors, various mechanisms resulting inloss ofthenormal p53genefunction havebeen implicated intumorigenesis. Observed aberrations ofp53 include genomic rearrangement (15), homozygous deletions (15,16), andLOH withconcomitant point mutations ina highly conserved region oftheremaining p53allele (3,17). Hereweconfirm theobservation (7,8)that LOH onthe short armofchromosome 17isafrequent allelic loss inbreast cancers. We foundthatthis losscorrelated withhighbro- modeoxyuridine (BrdUrd) labeling indexandDNA aneu- ploidy, characteristics ofaggressive tumorbehavior invivo (for review, seeref. 18). However, mutations ofthep53gene wererarely detected inthese breast cancers andthefew cancers showing mutations didnotcorrelate withthe17p LOHorhigh labeling index. Therefore, thelinkage between LOH at17pandcertain parameters ofaggressive disease appears tobeindependent ofDNA aberrations inthecon- served region ofthep53gene.