To bleed or not to bleed. A prediction based on individual gene profiling combined with dose-volume histogram shapes in prostate cancer patients undergoing three-dimensional conformal radiation therapy.
OBJECTIVE
The main purpose of this work was to try to elucidate why, despite excellent rectal dose-volume histograms (DVHs), some patients treated for prostate cancer exhibit late rectal bleeding (LRB) and others with poor DVHs do not. Thirty-five genes involved in DNA repair/radiation response were analyzed in patients accrued in the AIROPROS 0101 trial, which investigated the correlation between LRB and dosimetric parameters.


METHODS
Thirty patients undergoing conformal radiotherapy with prescription doses higher than 70 Gy (minimum follow-up, 48 months) were selected: 10 patients in the low-risk group (rectal DVH with the percent volume of rectum receiving more than 70 Gy [V70Gy] < 20% and the percent volume of rectum receiving more than 50 Gy [V50Gy] < 55%) with Grade 2 or Grade 3 (G2-G3) LRB, 10 patients in the high-risk group (V70Gy > 25% and V50Gy > 60%) with G2-G3 LRB, and 10 patients in the high-risk group with no toxicity. Quantitative reverse-transcriptase polymerase chain reaction was performed on RNA from lymphoblastoid cell lines obtained from Epstein-Barr virus-immortalized peripheral-blood mononucleated cells and on peripheral blood mononucleated cells. Interexpression levels were compared by using the Kruskal-Wallis test.


RESULTS
Intergroup comparison showed many constitutive differences: nine genes were significantly down-regulated in the low-risk bleeder group vs. the high-risk bleeder and high-risk nonbleeder groups: AKR1B1 (p = 0.019), BAZ1B (p = 0.042), LSM7 (p = 0.0016), MRPL23 (p = 0.015), NUDT1 (p = 0.0031), PSMB4 (p = 0.079), PSMD1 (p = 0.062), SEC22L1 (p = 0.040), and UBB (p = 0.018). Four genes were significantly upregulated in the high-risk nonbleeder group than in the other groups: DDX17 (p = 0.048), DRAP1 (p = 0.0025), RAD23 (p = 0.015), and SRF (p = 0.024). For most of these genes, it was possible to establish a cut-off value that correctly classified most patients.


CONCLUSIONS
The predictive value of sensitivity and resistance to LRB of the genes identified by the study is promising and should be tested in a larger data set.
Valdagni
Riccardo
R
Prostate Program, Fondazione IRCCS-Istituto Nazionale dei Tumori, Milano, Italy. riccardo.valdagni@istitutotumori.mi.it
Rancati
Tiziana
T
Ghilotti
Marco
M
Cozzarini
Cesare
C
Vavassori
Vittorio
V
Fellin
Gianni
G
Fiorino
Claudio
C
Girelli
Giuseppe
G
Barra
Salvina
S
Zaffaroni
Nadia
N
Pierotti
Marco Alessandro
MA
Gariboldi
Manuela
M
D002460:Cell Line; D004260:DNA Repair / Q000235:genetics*; D015536:Down-Regulation; D006471:Gastrointestinal Hemorrhage / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D012313:RNA / Q000302:isolation & purification; D011832:Radiation Injuries / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal; D012002:Rectal Diseases / Q000235:genetics*; D012007:Rectum / Q000528:radiation effects; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden
D012313:RNA