Somatic mosaicism of androgen receptor CAG repeats in colorectal carcinoma epithelial cells from men.
BACKGROUND
The X-linked human androgen receptor gene (AR) contains an exonic polymorphic trinucleotide CAG. The length of this encoded CAG tract inversely affects AR transcriptional activity. Colorectal carcinoma is known to express the androgen receptor, but data on somatic CAG repeat lengths variations in malignant and normal epithelial cells are still sporadic.


METHODS
Using laser capture microdissection (LCM), epithelial cells from colorectal carcinoma and normal-appearing mucosa were collected from the fresh tissue of eight consecutive male patients undergoing surgery (mean age, 70 y; range, 54-82). DNA isolated from each LCM sample underwent subsequent PCR and DNA sequencing to precisely determine AR CAG repeat lengths and the presence of microsatellite instability (MSI).


RESULTS
Different AR CAG repeat lengths were observed in colorectal carcinoma (ranging from 0 to 36 CAG repeats), mainly in the form of multiple shorter repeat lengths. This genetic heterogeneity (somatic mosaicism) was also found in normal-appearing colorectal mucosa. Half of the carcinoma cases examined tended to have a higher number of AR CAG repeat lengths with a wider range of repeat size variation compared to normal mucosa. MSI carcinomas tended to have longer median AR CAG repeat lengths (n = 17) compared to microsatellite stable carcinomas (n = 14), although the difference was not significant (P = 0.31, Mann-Whitney test).


CONCLUSIONS
Multiple unique somatic mutations of the AR CAG repeats occur in colorectal mucosa and in carcinoma, predominantly resulting in shorter alleles. Colorectal epithelial cells carrying AR alleles with shorter CAG repeat lengths may be more androgen-sensitive and therefore have a growth advantage.
Di Fabio
Francesco
F
Colon and Rectal Surgery, McGill University, Montreal, Quebec, Canada.
Alvarado
Carlos
C
Gologan
Adrian
A
Youssef
Emad
E
Voda
Linda
L
Mitmaker
Elliot
E
Beitel
Lenore K
LK
Gordon
Philip H
PH
Trifiro
Mark
M
D002277:Carcinoma / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D004847:Epithelial Cells / Q000473:pathology; D005091:Exons; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D053842:Microsatellite Instability; D009030:Mosaicism; D011110:Polymorphism, Genetic; D011944:Receptors, Androgen / Q000235:genetics*; D012016:Reference Values; D018911:Trinucleotide Repeats
D011944:Receptors, Androgen