Sex Chromosome Alterations Associate with Tumor Progression in Sporadic Colorectal Carcinomas

Abstract

Purpose: The X and Ychromosomes have been associated with malignancy in different types of human tumors. This study attempts to determine the involvement of X chromosome and pseudoautosomal regions (PAR) in sporadic colorectal carcinogenesis. Experimental Design: An allelotyping of X chromosome in 20 premalignant and 22 malignant sporadic colorectal tumors (CRC) from female patients and an analysis of losses [loss of heterozygosity (LOH)] on PARs from 44 CRCs and 12 adenomas of male patients were carried out. In male tumors, a fluorescence in situ hybridization analysis was done to identify which sex chromosome was possibly lost. Results: The LOH frequency in female CRCs was 46% with higher incidence in patients with tumor recurrence than in those who were disease-free (P < 0.01) and with a significant difference from adenomas (11%; P < 0.0001).The LOH rate of PARs in male CRCs was 37% with a frequency significantly higher in patients with recurrence (P < 0.03). These results were maintained also when data from PARs of all 66 male and female patients were cumulated (P < 0.05). LOH in PARs was significantly correlated with LOH at 5q (P < 0.01) and 18q (P < 0.01), early and late events, respectively, in colorectal carcinogenesis. Fluorescence in situ hybridization analysis in male patients with extensive PAR LOH revealed a preferential loss of theYchromosome. Conclusions: Our data suggest a role for sex chromosome deletions in the malignant progression of sporadic CRCs and support the presence in the PARs of putative tumor suppressor genes involved in the progression of human sporadic CRCs.The human X and Y chromosomes are morphologically and genetically distinct. The X chromosome is large and euchromatic and contains almost 1,000 genes (1), whereas the Y chromosome is small and heterochromatic and contains at least 160 genes (2, 3). A number of genes retain copies on both X and Y chromosomes and escape the inactivation that affects most X-linked genes in somatic cells (4). At both ends of sex chromosomes, X-Y homologous regions are present: these are pseudoautosomal regions (PAR) that pair regularly at male meiosis and undergo recombination (5). The unique biology of these regions has attracted considerable interest because of the identification of new tumor suppressor genes whose alterations may play a role in the development and progression of human tumors.X chromosome was found to be involved in carcinogenesis and the malignant progression of different types of human tumors, and an increasing number of potentially responsible genes have been identified (1). In particular, gains or deletions have been associated with tumoral progression, the presence of metastases, and worse prognosis in tumors of the breast (6), ovary (7), and uterine cervix (8) and in papillary renal cell carcinomas (9). With regard to Y chromosome, deletions have been shown to be involved in prostate cancer (10 -14), male breast carcinomas (15 -17), and pancreatic adenocarcinomas (18).In previous studies done in our laboratory on ne...

Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells

“…At the present time, however, it is difficult to know, which genes are of significance in feminized CRCs due to the large genomic areas affected by the X chromosomal aberrations. With respect to the Y chromosome losses in male CRC observed here, other studies also support our findings [11,12,48]. …”

Sexual dimorphism in cancer

“…Loss of the entire Y chromosome (LOY) has been reported with various frequencies in prostate [133][134][135] , pancreatic 136 , colorectal 137 and bladder 138 , which has also a strong male prevalence. Short arm deletions have also been found in numerous cancer types 139 (http://cgap.nci.nih.gov/Chromosomes/Mitelman).…”

Intracranial germ cell tumors: association with Klinefelter syndrome and sex chromosome aneuploidies

“…In ICGCTs, the gain of X/Y chromo- somes in the tumors could result in gene dosage effects caused by genomic rearrangements as well as by mutations in yet unknown genes leading to activation of oncogenes or loss of function of tumor suppressor genes (Skaletsky et al, 2003;Spatz et al, 2004;Hanks and Rahman, 2005). Recent data have shown that some sporadic colorectal cancers exhibit X chromosome abnormalities suggesting the participation of putative tumor suppressors within PARs (pseudoautosomal regions) (Bottarelli et al, 2007). In summary, our findings support the notion that ICGCTs are associated with KS and emphasize that sex chromosome aneuploidies participate in both tumorigenesis and cancer progression.…”