The risk of lung and breast cancer is significantly increased after therapy for 
Hodgkin's disease (HD), but there are few data that describe the molecular 
profiles of these tumors. We investigated the genetic abnormalities in second 
primary lung (n = 19) and breast cancers (n = 19) that follow therapy for HD 
("post-HD cancers") and compared these with changes observed in corresponding 
tumor types (57 lung and 20 breast cancers) arising in the general population 
("sporadic cancers"). DNA obtained from archival tissues was examined using 
PCR-based analyses for loss of heterozygosity and microsatellite alterations 
(MAs) at several chromosomal regions, TP53 and K-ras gene mutations, and 
frameshift mutations at minisatellite sequences at the coding regions of several 
genes (TGF-betaRII, IGFIIR, BAX, hMSH6, and hMSH3). The occurrence of loss of 
heterozygosity at all chromosomal regions taken together and frequencies at most 
individual areas were similar for the post-HD and sporadic cancers for both lung 
and breast sites. The overall frequency of MAs in the post-HD tumors was 
substantially greater (lung, 2.4-fold, P = 0.004; breast, 4.2-fold, P = 0.16) 
than that in the respective sporadic cancers. No differences in the pattern of 
TP53 and K-ras mutations were detected between post-HD and sporadic cancers. No 
mutations were detected at the minisatellite sequences examined. MAs, which 
reflect widespread genomic instability, occur at greatly increased frequency in 
post-HD lung and breast cancers. Although the mechanisms underlying the 
development of increased MAs are unknown, they have been associated with 
immunosuppression and radiation exposure. Future research should address the 
role that MAs, as well as other influences, may play in the development of 
neoplasias that occur after therapy for HD.