Microsatellite instability analysis of bilateral breast tumors suggests treatment-related origin of some contralateral malignancies.

PURPOSE: High-frequency microsatellite instability (MSI-H) occurs frequently in colorectal cancers and some other tumor types, but is very uncommon in breast cancer. In the earlier study devoted to microsatellite analysis of allelic imbalances, the authors accidentally detected several MSI-H tumors in patients with the bilateral form of breast cancer (biBC). The present study was designed to examine this unexpected phenomenon in more detail. METHODS: All DNA samples were tested by the standard panel of MSI-specific markers BAT25, BAT26, BAT40, D5S346, and D17S250. If the tumor was unstable for at least one marker, or PCR amplification was not successful for any of the listed above loci, the analysis of additional five dinucleotide markers (D1S225, D11S4167, D22S272, D22S1166, and D3S3527) was performed. Tumors showing instability in > or = 30% loci were classified as MSI-H. RESULTS: In biBC group, MSI-H status was detected in 6/60 (10%) contralateral tumors, but in 0/50 (0%) first malignancies (P = 0.021) and only in 1/22 (5%) synchronous biBC (P = 0.434). None of 52 unilateral breast cancers showed MSI-H status. Shifts of mononucleotide markers were revealed in four second carcinomas from biBC patients but in none of the breast tumors from other categories. CONCLUSIONS: MSI-H is detected with a noticeable frequency in bilateral but not in unilateral breast cancers. Preferable occurrence of MSI-H in second metachronous tumors from biBC patients allows to hypothesize that the development of some contralateral breast neoplasms is casually related to the adjuvant treatment of the initial malignancy.

Expression of inhibitor of apoptosis proteins in small- and non-small-cell lung carcinoma cells.

Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cells both initiate apoptotic signaling, resulting in caspase activation, after treatment with anti-cancer agents. However, in contrast to SCLC cells, NSCLC cells do not fully execute apoptosis. The apoptotic process in NSCLC cells seems to be blocked downstream of caspase activation, thus the failure of NSCLC cells to execute apoptosis could result from inhibition of active caspases by inhibitor of apoptosis proteins (IAPs). Here we investigate the mRNA and protein expression of IAPs in a panel of SCLC and NSCLC cell lines. The NSCLC cell lines had a stronger cIAP-2 expression at both mRNA and protein levels, while the SCLC cell lines had a higher level of XIAP protein. Expression of cIAP-1, cIAP-2, and XIAP, the most potent caspase inhibitors, was further investigated in three lung carcinoma cell lines after treatment with 8 Gy of ionizing radiation or etoposide (VP16). In response to treatment, the level of IAPs was not altered in a way that explained the differences in cellular chemo- and radiosensitivity. The intracellular localization of IAPs was analyzed in untreated and treated lung cancer cells. Surprisingly, we found that cIAP-2 was mainly detected in the mitochondrial fraction, although the function of this protein in mitochondria is unknown. No major relocalization of IAPs was observed after treatment. Taken together, these results indicate that IAPs alone are not the main factor responsible for the resistance of NSCLC cells to treatment.

Concordance of allelic imbalance profiles in synchronous and metachronous bilateral breast carcinomas.

Bilateral breast cancer (biBC) is a common form of breast cancer; however, it has not been subjected to systematic comparative genetic studies. We allelotyped 28 biBCs on 14 chromosomal arms, addressing 2 lines of questions: (i) does comparison of genetic profiles disclose contralateral metastases misdiagnosed as second primaries? and (ii) do shared environmental and host factors drive the development of true biBC along similar genetic routes? Allelotyping provided unambiguous proof for distinct clonality in 23 of 28 cases. In another 4 biBCs, the genotyping data did not exclude the hypothesis of metastatic spread, whereas clinical and histologic data were in favor of bilaterality. Thus the question of clonality remained open only for 1 case, in which the paired tumors shared both histologic features and allelotypes. We conclude that the vast majority if not all biBCs are of independent clonal origin. Next, we assessed the similarity of genetic pathways in distinct categories of biBC. It was assumed that the coexistence of allelic imbalance (AI) in 1 tumor and retention of heterozygosity (N) in the contralateral neoplasm corresponds to the distinct genetic profiles, whereas the remaining combinations (AI/AI or N/N) suggest a match of allelic status for a given polymorphic marker. When these allelic matches were pooled, it turned out that synchronous biBC displayed a significantly higher similarity score than metachronous biBC (64/77 [83%] vs. 162/267 [61%]; p = 0.0003). In addition, an increased similarity of allelic profiles was observed in the premenopausal biBC (76/101 [75%]) compared with postmenopausal cases (111/173 [64%]) or tumor pairs separated by the onset of menopause (39/70 [56%]; p = 0.014). Overall, our data suggest that sharing natural histories of the disease, which is more evident in synchronous and/or premenopausal forms of biBC, may result in a similarity of molecular portraits in bilateral breast tumors.