Effects of radiation on levels of DNA damage in normal non-adjacent mucosa from colorectal cancer cases.
OBJECTIVE
Defects in DNA repair pathways have been linked with colorectal cancer (CRC). Adjuvant radiotherapy has become commonplace in the treatment of rectal cancer however it is associated with a higher rate of second cancer formation. It is known that radiation results in DNA damage directly or indirectly by radiation-induced bystander effect (RIBE) by causing double-strand breaks (DSBs). The majority of work in RIBE has been performed in cell lines and limited studies have been in or ex vivo.


METHODS
The first study aim was to examine by immunohistochemistry, levels of DSB (expression of the protein MRE11) in normal colonic tissue outside the irradiated field post neo-adjuvant radiotherapy (group 1). These levels were compared to (a) irradiated tumour tissue post neo-adjuvant radiation within the same group, (b) a CRC patient group (group 2) who had not undergone neo-adjuvant radiotherapy and (c) a non-cancer patient group (group 3). The second aim was to determine if MRE11 expression levels were related to survival or radio-sensitivity post neo-adjuvant radiotherapy.


RESULTS
There was a highly significant increase in MRE 11 expression in group 1 versus groups 2 and 3 (p < 0.001). There was no association between MRE11 levels and survival or radio-sensitivity.


CONCLUSIONS
Our findings show radiotherapy causes DSBs at significantly higher levels in normal colonic mucosa of patients post neo-adjuvant treatment which may represent RIBE. If this damage remains unrepaired, increased levels of genomic instability may contribute to the higher occurrence of second cancers in patients treated post neo-adjuvant radiotherapy.
Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
Juliette
J
Sheridan
Miriam
M
Tosetto
Julie
J
Gorman
Diarmuid
D
O'Donoghue
Kieran
K
Sheahan
John
J
Hyland
Hugh
H
Mulcahy
David
D
Gibbons
Jacintha
J
O'Sullivan
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024201:Bystander Effect; D003106:Colon / Q000378:metabolism* / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D004268:DNA-Binding Proteins; D005240:Feasibility Studies; D005260:Female; D042822:Genomic Instability / Q000235:genetics / Q000528:radiation effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D000076228:MRE11 Homologue Protein; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D012007:Rectum / Q000378:metabolism* / Q000528:radiation effects; D046888:Tissue Array Analysis; D055815:Young Adult
D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein