Loss of heterozygosity on chromosome 10q is associated with earlier onset sporadic colorectal adenocarcinoma

Abstract

Recent studies have shown that loss of heterozygosity (LOH) on chromosome 10q is a frequent event in a number of tumour types including colorectal cancers. Because previous studies have used markers located mainly distally on chromosome 10, we have examined 114 sporadic colorectal adenocarcinomas for LOH using a panel of 9 highly polymorphic microsatellite markers spanning the long arm of chromosome 10. Using microdissected tumour material, LOH of one or more chromosome 10q markers was a frequent event (75 of 114; 66%). The highest frequency of loss (42 of 96; 44%) was observed at the marker D10S1790 located at 10q21.1. The mean age of presentation, of patients with LOH of D10S1790 was significantly (p ‫؍‬ 0.0006) lower (67.1 years) compared to patients with retention of this marker (73.5 years). When we compared frequency of loss at this marker in patients presenting before 70 years of age (68%) to those above 70 years (23%) we observed a significant difference Key words: chromosome 10q; LOH; sporadic colorectal adenocarcinoma; TSG; tumor progressionColorectal adenocarcinoma is the second most common cause of cancer related death in the Western world. The majority of colorectal cancers are considered sporadic and present in the 7th and 8th decades of life, whereas hereditary colorectal adenocarcinoma accounts for approximately 10% of all cases and usually presents before the age of 50 years. 1 The initiation and progression of sporadic colorectal tumors has been described as a multi-step etiology involving the progressive loss of tumour suppressor function and concomitant inappropriate oncogene activation resulting in the deregulation of controlled cellular proliferation. 2 Frequent loss of heterozygosity (LOH) has been shown in regions harboring known tumour suppressor genes including 5q21(APC), 17p13(p53) and 18q21(DCC) involved in the development of sporadic colorectal adenocarcinoma. 2 Studies have shown frequent LOH on chromosome 10q in several tumour types including malignant gliomas, 3 malignant melanomas, 4 prostate, 5,6 endometrial, 7 breast 8,9 and bladder cancer. 10 Early studies of this chromosome, however, showed infrequent loss in colorectal cancer. 11 A subsequent allelotyping study 12 of sporadic colorectal adenocarcinomas showed that LOH on chromosome 10q was an infrequent event, however, this study only investigated a single locus (10q25-26). More recently Frayling et al. 13 using a more centromeric marker (D10S220) showed frequent LOH (37%) in sporadic colorectal adenocarcinomas on 10q11-21 suggesting the presence of a tumour suppressor gene (TSG) in this region. The presence of a TSG in this region is supported by findings in other tumour types including renal, 14 chondrosarcomas 15 and malignant glioma 3 that have shown frequent LOH at 10q11-21.Recently a TSG called PTEN, MMAC1 or TEP1 16 -18 has been localized to the chromosomal loci 10q23.3, loss and concomitant mutation in the retained PTEN allele have been shown in glioblastomas, 19 malignant melanoma, 20,21 squamous cell lung carcino...

Loss of Heterozygosity on Chromosome 10p14–p15 in Colorectal Carcinoma

“…In CRC, LOH on chromosomes 1p, 3p, 4p, 5q, 8p, 10q, 11p, 11q, 13q, 14q, 15q, 17p, 17q, 18q, 20q and 22q has been reported. For example, Popat et al [17] detected a high frequency of LOH of 15q14-q22 (D15S971, 34%), Ruivenkamp et al [21] noted a high frequency of LOH on 11p11 (PTPRJ, 71%), Fawole et al [11] found a high frequency of LOH on 10q21.2 (D10S1790, 44%) and Park et al [18] revealed a high frequency of LOH on 15q21.1 (D15S129, 44%, and D15S968, 44%).…”

Fine mapping of chromosome 10q deletions in mycosis fungoides and sezary syndrome: Identification of two discrete regions of deletion at 10q23.33–24.1 and 10q24.33–25.1

“…Chromosome 10q is a common site of allelic loss in malignancy, with loss of heterozygosity (LOH) detected in several tumor types including malignant gliomas (Karlbom et al, 1993), melanomas (Herbst et al, 1994), and endometrial (Peiffer et al, 1995), breast (Singh et al, 1998), thyroid (Yeh et al, 1999), colorectal (Fawole, 2002), hepatocellular (Fujiwara et al, 2000), renal cell (Alimov et al, 1999), prostate (Gray et al, 1995), and bladder (Kagan et al, 1998) carcinomas, as well as in B‐cell non‐Hodgkin's lymphomas (Butler et al, 1999). These malignancies all have an as‐yet‐undefined region of allelic loss at 10q22–26.…”

Disruption of Sphingosine 1-Phosphate Lyase Confers Resistance to Chemotherapy and Promotes Oncogenesis through Bcl-2/Bcl-xL Upregulation

“…Interestingly, the SGPL1 gene, which encodes SPL, has been reported to be significantly downregulated in human colon cancer tissues compared with normal tissues (22). Moreover, the human SGPL1 gene maps to chromosomal region 10q21 (23), which is deleted or mutated in many human tumor types (24)(25)(26). Altogether, these observations suggest that loss of SPL expression might potentiate cancer cell proliferation and contribute to tumorigenesis; this, however, remains to be demonstrated.…”