Predicting treatment outcome

Although leukaemic subtypes with poor prognosis have a decreased tendency to undergo apoptosis, gene-expression-profiling studies have identified few differentially expressed apoptosis genes. William Evans, Rob Pieters and colleagues therefore analysed the expression of 70 key apoptosis genes in leukaemic cells taken from 190 children with acute lymphoblastic leukaemia (ALL).

The authors found differences between the expression profiles of ALL subtypes: 44 genes were differentially expressed in T-lineage versus B-lineage ALL, 22 genes differed in hyperdiploid versus non-hyperdiploid B-lineage ALL, 16 genes differed in TEL–AML1+ versus TEL–AML1− B-lineage ALL, and 13 genes differed in E2A-rearranged versus E2A-germline B-lineage ALL. Next, they looked at the differences in expression of apoptotic genes between drug-sensitive and -resistant patients in the B-lineage ALL group. Although no probe sets were associated with resistance to vincristine or daunorubicin, MCL1 and DAPK1 were associated with prednisolone resistance, and BCL2L13, HRK and TNF were associated with resistance to L-asparaginase.

BCL2L13 was the only gene independently associated with treatment outcome. The 5-year probability of disease-free survival was 85% for patients with low expression of BCL2L13 and 66% for patients with high expression. These findings were validated on an independent cohort of 92 patients treated with the same drugs but on a different protocol.

BCL2L13 has pro-apoptotic activity in cell lines, so it is surprising that high expression is associated with drug resistance in this study. The authors suggest that BCL2L13 might have a different apoptotic role in primary leukaemic cells, or that there might be an anti-apoptotic splice variant. Prospective validation is now required to establish BCL2L13 expression as a true prognostic factor in childhood ALL. ORIGINAL REFERENCE Holleman, A. et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia. Blood 107, 769–776 (2006)

Predicting disease progression

The role of ERBB2 (also known as HER2/NEU) is best characterized in breast cancer progression, but overexpression of ERBB2 has also been observed in patients with metastatic androgen-independent prostate cancer. Iman Osman et al. analysed the serum of 279 patients enrolled in a prospective serum bank using the FDA-approved Immuno-1 ERBB2 assay.

Increased serum ERBB2 was observed in 13.3% of patients (cut-off value for normal serum was 14 ng ml−1). There was a significant difference between serum ERBB2 concentrations in patients with and without metastases, and the risk of cause-specific death increased with each unit increase in serum ERBB2. These data indicate that this test could be used to identify potential candidates for anti-ERBB2 therapy. ORIGINAL REFERENCE Osman, I. et al. Serum levels of shed HER2/NEU protein in men with prostate cancer correlate with disease progression. J. Urol. 174, 2174–2177 (2005)