Patterns of LOH in Cancers

LOH has been detected on all chromosomes. Table 11.1 summarizes some associations between LOH and cancers, and Table 11.2 lists individual genes that are targets for allele loss in cancers. The following sections outline in more detail selected research on LOH in disease, with particular focus on known or putative tumor suppressor genes and their role in disease initiation or progression.

LOH at 1p

LOH at 1p has been associated several cancers, including lung,48-51 colorectal,52 and gastrointestinal stromal tumors5 3 and hepatocellular carcinoma.54 LOH at 1p36 was found to

Table 11.1. Associations between loss of heterozygosity (LOH) and some cancers.

Chromosome

Cancers

References

1p

Oligodendroglial tumors

9

Hepatocellular carcinoma

54

2p

Breast carcinoma

136

3p

Eye, central nervous system, kidney,

137

pancreas, and other tissues

Esophageal adenocarcinoma

68

Lung cancer

41

5q

Pulmonary large cell neuroendocrine

14

carcinoma

6p

Cervical carcinoma

8

Acinic cell carcinoma of the parotid

10

gland

8q

Hepatocellular carcinoma

54

9

Bladder cancer

138

10q

Primary and secondary glioblastoma

139

Small cell lung cancer

11, 116

11p

Epithelial ovarian carcinoma (invasive)

12

16q

Ductal breast carcinoma

140

18q

Esophageal carcinoma

68

22q

Secondary glioblastoma

13

Table 11.2. Individual genes associated with loss of heterozygosity (LOH) in disease .

Gene

Disease

References

GPX1 (selenium-containing antioxidant enzyme) Von Hippel-Lindau (VHL) (inherited cancer predisposition) BRCA1, -2 HRPT2 gene CDH13 FHIT gene

Head and neck, lung, breast, 141 and colon cancers

Multiple organs can develop 137 cancer in VHL patients

Breast carcinoma 142143

Sporadic renal tumor 144

Ductal breast carcinoma 140 Lung, gastric, and cervical 41,145,146 cancer be a prognostic indicator for decreased overall survival in hepatocellular carcinoma patients.54 1p36 encompasses several candidate tumor suppressor genes, including p73 and tumor necrosis factor receptor-2 (TNFR2).48 P73 is a member of the p53 family and is capable of mimicking some of the effector functions of p53, including induction of permanent growth arrest and promotion of apoptosis.55 The TNFR2 binds to and mediates signals from lymphotoxin-a (LTa), lymphotoxin-b (LTb), and TNF, three cytokines associated with receptor-mediated induction of cell death.56

In oligodendroglial tumors, LOH at 1p is associated with better prognosis.57 Further characterization of these tumors revealed that in cells with LOH at 1p, the expression of GLUT-1, a component of the glucose transport machinery, was reduced compared to cells that retained heterozygosity at 1p. Stockhammer et al57 speculated that the disappearance of GLUT-1 in cells might affect the tumor's sensitivity to chemotherapy drugs. Further study is needed to elucidate the details, but this research highlights how LOH detection can inform treatment planning.

LOH at 3p

The best described and best documented gene targeted for LOH in nearly all lung cancers is the fragile histidine triad (FHIT), on 3p14. LOH at 3p14 is strongly correlated with exposure to tobacco smoke and occurs early in carcinogen-exposed lung epithelium.20,58-63 The linkage between tobacco carcinogen exposure and LOH on chromosome 3p is particularly strong in individuals who initiated smoking at an early age.37 In two studies, LOH at a locus near the hMLH1 gene on chromosome 3p21 was correlated strongly with early age of smoking initiation and with the level of DNA adducts.35,64 The FHIT gene encodes a small protein with diadenos-ine triphosphate hydrolase activity, but its tumor suppressor activity is presumed to be independent from this enzymatic activity.62 The microregion of the FHIT gene is frequently targeted for LOH in tumors; however, this association alone does not confirm tumor suppressor activity. Evidence for FHIT as a tumor suppressor gene includes the observations that FHIT gene-deficient mice are more susceptible to carcinogen-induced tumor formation/5 and that expression of FHIT suppresses the growth of cancer cells through promotion of apoptosis and growth inhibition.66

FHIT genetic and protein losses have been shown in tumors from other cancers in addition to lung: esophageal/7-69 breast,70 and kidney.71,72 In addition, other tumor suppressor gene candidates targeted by LOH are located in the same region (3p12-3p22) as the FHIT gene. These other genes include transforming growth factor receptor beta-2 (TGFPR2), MLH/ HNPCC2, deleted in lung cancer-1 (DLC1), RASSF1A, retinoic acid receptor-beta (RARb), and BRCA1-associated protein-1 (bAP1).5048,58,59,7374 LOH at 3p25, which includes the von Hippel-Lindau (VHL) locus, has also been reported as a frequent event in several cancers.20,75

LOH at 4q

LOH at 4q has been associated with breast/6 cervical,77-79 mouth,80 throat,81-83 bladder,84-86 colon,87 88 lung,488990 and liver cancers91-94 as well as acute lymphoblastic leukemia.95 Jiang et al87 further analyzed 4q LOH patterns in colorectal carcinoma tumors from 83 patients to evaluate relationships between LOH patterns and clinicopathological features. LOH in 4q13.2 was significantly higher in tumors larger than 5 cm in diameter. LOH in 4q21.23 was significantly associated with metastasis. Suspected tumor suppressor genes are located in each region, but cause-and-effect relationships between specific genes and tumor diameter or metastasis have not yet been established.

LOH at 5q

SCLC is characterized by a high frequency of LOH at 5q32-ter, and although no candidate tumor suppressor genes have been identified, the SPARC (secreted protein acidic and rich in cysteine) gene maps to 5q32 and has been associated with LOH in idiopathic pulmonary fibrosis (IPF).96 SPARC, a protein involved in the regulation of cell adhesion and growth, is methylated aberrantly in lung cancers" Although nons-mall cell lung cancer (NSCLC) has not been associated with LOH at 5q32, there is often LOH at 5q21.3-31, a region that contains several key tumor suppressor genes including MCC (mutated in colorectal cancer), APC (adenomatous polypo-sis coli), and IRF1.48 LOH at 5q21 has been documented in preneoplastic cells, suggesting it may be an early genetic change, and it is more prevalent in squamous cell carcinomas compared to adenocarcinomas.98,99 However, as in other LOH events, studies have failed to provide strong correlation between these events and patient prognosis. In lung cancer, it appears that LOH at the APC locus is relatively frequent but that the mechanism by which the remaining allele is silenced is usually promoter methylation, rather than mutation.100

LOH at 8p

LOH on chromosome 8p21-23 is a frequent event in many cancers and is often associated with more aggressive disease. 1 01,102 Intense research has focused on 8p21 to identify tumor suppressor genes and look for connections between LOH and clinical characteristics. Shi et al103 investigated DBC2 (deleted in breast cancer 2) expression in bladder cancer. In these tumors, LOH was not frequent, but they discovered that promoter methylation caused downregula-tion of DBC2 expression, mimicking the effect of LOH at DBC2 observed in other cancers.

In head and neck squamous cell cancer (SCC), 8p21-22 was the most frequent site of LOH.104 Ye et al104 investigated expression of another candidate tumor suppressor gene identified in the region, MTUS1 (mitochondrial tumor suppressor gene 1), and found downregulation of transcription and mutations in exon-coding sequences. Coon et al102 found that LOH in a region of 8p that included 8p21 was strongly associated with shorter survival in head and neck SCC patients. Ye et al. discovered that LOH was observed mainly in invasive and metastatic SCC

LOH at 8p21 is a frequent and early occurrence in NSCLC, believed to occur after LOH events at 3p and 9p105,106 and hepatocellular carcinoma.54 Despite consistent observations of LOH in this region in lung cancer, specific tumor suppressor genes have not been mapped to 8p21-23 and implicated in the development and progression of lung cancer. LOH at 8p21-23 is also a frequent event in hepa-tocellular carcinoma (HCC), and a gene encoding a growth inhibitory protein, HCRP1 (hepatocellular carcinoma related protein-1) has been mapped to that area and implicated in HCC.107

LOH at 9p

Chromosome 9p is frequently altered in NSCLC, not only by LOH but also by homozygous deletion and gene silencing via promoter hypermethylation.48,108,109 The redundancy in mechanisms aimed at silencing genes in this region and the prevalence of these alterations in smoke-exposed preneoplastic epithelium point to the importance of 9p in the development of lung cancer. The gene most frequently identified in LOH studies of 9p (9p21) in NSCLC is P16™K4A, a gene that encodes a cell-cycle protein which inhibits CDK4, CDK6, and cyclin-dependent phosphorylation of the Rb gene product.110-112 Loss of the P16I NK4A gene effectively removes key negative regulation of the cell cycle at the G1- ^ S-phase transition.113 Interestingly, experimental evidence suggests that the silencing of the remaining P16I NK4A allele after allelic loss is predominantly caused by epigenetic methylation rather than mutation.114

LOH at 10q

LOH at 10q22-23 is a frequent observation in SCLC. Although no tumor suppressor genes in this region have been definitively associated with lung cancer, multiple studies have identified LOH targeted to the PTEN/MMAC locus at 10q 23.115-117 The encoded PTEN protein is a lipid phos-phatase that negatively regulates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway. Loss of PTEN function results in reduced apoptosis and stimulation of cellular proliferation and migration.117

LOH at 13q

Chromosome 13q12-14 is a prevalent hotspot for LOH in many cancers. The retinoblastoma (RB1) gene is a well-characterized tumor suppressor gene, at 13q12, the product of which is a key regulator of entry into S phase of the cell cycle. 1 18 The critical pathway regulated by RB, p16 1 NK$A i cyclin-D1, and cyclin-dependent kinases (CDKs) is disturbed, usually via multiple components, in nearly every case of lung cancer, thus rende-ring cells insensitive to the signaling involved in regulating mitosis.118 LOH on 13q12.1-13.1 can be identified in cells obtained from bronchial washing specimens from SCLC and NSCLC patients and is proposed as one of a set of markers that could be used for early detection of lung cancer. i 19 Another gene targeted to 13q12-14 is BRCA2, a gene associated with cancer susceptibility and with possible linkages to p53 in the context of DNA damage repair.120

LOH at 17p

The TP53 gene at 17p13 is the most frequently altered tumor suppressor gene in human cancers. TP53 is targeted by mutation, methylation, and homozygous deletion, in addition to LOH. The observations of redundant mechanisms of TP53 inactivation and frequency of LOH at TP53 gene point to its critical role in the development of malignant disease. TP53 modulates a broad network of cellular responses, including cell-cycle arrest, apoptosis, DNA repair, cellular senescence, and inflammation, and therefore plays a central role in homeostasis.121 TP53 mutations can be found in precancer-ous lesions, but to date studies of LOH at 17p indicate that allelic loss of TP53 occurs during disease progression, after LOH events on chromosome 3p.122

LOH at 19p

LOH at 19p13.3 is a very frequent event in NSCLC but is not targeted in SCLC.48 One tumor suppressor gene candidate residing at this locus is STK11/LKB1, a gene implicated in Peutz-Jeghers syndrome. i23,124 LOH at this locus has been documented in breast cancer and in brain metastases from a variety of human cancers.124,125

Summary

Abundant research has demonstrated that certain patterns of LOH are seen in multiple cancers. Other LOH loci are seen in only certain cancers or occur at a particular stage of disease progression. The availability of high-throughput assays and high-resolution LOH probes is increasing the breadth and depth of studies to elucidate the contribution of LOH to disease, prognosis, or effectiveness of treatment regimens. Currently, there are few loci for which a cause-and-effect relationship to cancer has been established. However, researchers are now armed with an arsenal of tools with which to discover the temporal sequence of LOH events in tumor initiation and progression and contribution of specific tumor suppression genes to cellular and tissue growth regulation.

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