Association between recurrence of sporadic colorectal cancer, high level of microsatellite instability, and loss of heterozygosity at chromosome 18q.
OBJECTIVE
Microsatellite instability and loss of heterozygosity of chromosomes 18q, 8p, and 4p are genetic alterations commonly found in colorectal cancer. We investigated whether these genetic markers allow for the stratification of patients with Stage II to III colorectal cancer into groups with different recurrence risks, and with different prognoses.


METHODS
Tumors of 113 patients were evaluated for loss of heterozygosity of chromosomes 18q, 8p, and 4p and for microsatellite instability by use of six microsatellite markers. Genetic alterations involving each of these genetic markers were examined for association with disease recurrences and survival.


RESULTS
Loss of heterozygosity of chromosomes 18q, informative in 96 percent of cases, in Stage III tumors was associated with higher risk of overall recurrence ( P< 0.001), local recurrence ( P< 0.001), distant metastases ( P< 0.001), decreased overall survival ( P= 0.002), and disease-free survival ( P< 0.001). The recurrence rates and survival rates among patients with Stage II colorectal cancer were independent of loss of heterozygosity of chromosome 18q. Stage III and loss of heterozygosity of chromosome 8p also were associated with a higher risk of recurrences when these factors were considered individually. In multivariate analysis, only loss of heterozygosity of chromosome 18q was independently associated with risk of recurrences ( P < 0.001) and with disease-free survival ( P= 0.001). No correlation was observed between microsatellite instability and recurrence rates. However, microsatellite instability was associated with improved overall survival ( P= 0.04) and with a longer disease-free interval ( P= 0.002). Only in five cases (16.7 percent) was it possible to perform resection of recurrences; two of these patients had microsatellite instability tumor. In no cases was it possible to resect recurrence of tumors with loss of heterozygosity of chromosome 18q.


CONCLUSIONS
Loss of heterozygosity of chromosome 18q is an informative genetic marker, which in resected Stage III colorectal cancer can be used to predict recurrences and survival. Microsatellite instability identified cases that, even in the case of recurrence, have a more favorable prognosis.
Sarli
Leopoldo
L
Department of Surgical Sciences, Section of General Surgical Clinics and Surgical Therapy, Parma University Medical School, Parma, Italy. leosarli@unipr.it
Bottarelli
Lorena
L
Bader
Giovanni
G
Iusco
Domenico
D
Pizzi
Silvia
S
Costi
Renato
R
D'Adda
Tiziana
T
Bertolani
Marco
M
Roncoroni
Luigi
L
Bordi
Cesare
C
D000368:Aged; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors
D005819:Genetic Markers