Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer

Abstract

Copy neutral loss of heterozygosity (cnLOH) is a common event in several human malignancies-positing this as a mechanism of carcinogenesis. However, the role of cnLOH in synchronous colorectal cancer (SCRC), a unique CRC subtype, is not well understood. The aim of this study was to establish a cnLOH profile of SCRC using a single-nucleotide polymorphism array (SNP-A), and to explore associations between cnLOH and the genomic landscape of frequently mutated genes in SCRC. Among 74 paired SCRC cases, the most frequently altered regions were 16p11.2-p11.1 (59.5%) and 11p11.2-p11.12 (28.4%). Notably, the 6q11.21-q11.22 region altered by cnLOH was uniquely associated with polyclonal SCRCs (p = 0.038). Together, our analysis suggests that inactivation of tumor suppressor genes and cnLOH are rare events among SCRC cases. This study defines distinct patterns of cnLOH in SCRC, and provides initial evidence of a role for cnLOH in SCRC etiology.

Loss of heterozygosity related to TMB and TNB may predict PFS for patients with SCLC received the first line setting

“…The loss of one of these gene copies, termed as loss of heterozygosity (LOH), is one of the most common genetic alterations in cancer [1]. LOH has been playing a pivotal role in cancer development [2]. For instance, LOH was found to be involved in the relapse of acute lymphoblastic leukemia [3].…”

Association of Mosaic Chromosomal Alterations and Genetic Factors with the Risk of Cirrhosis

“…the most frequent mutation cluster region was 16p11.2-p11.1 (59.5%), where CN-LOH was significantly associated with polyclonal synchronous colorectal cancers (p=0.038). 28 CN-LOH was also associated with the duplication of oncogenic mutations with concomitant loss of the normal allele in myeloid malignancies. 21 Therefore, combining mosaic mutations and genetic mutations is a more accurate way to achieve precise prediction of disease.…”

Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy

“…The establishment of LOH maps by cytogenetics [24] or, more recently, by genome-wide copy number analyses and genome sequencing, have enabled identification of chromosomal regions lost in different tumor types [25][26][27][28]. A study of~10 5 LOH events in 363 glioblastoma and 513 ovarian cancer samples revealed that LOH selectively occurs in early replicating regions, especially near RNA pol II-bound transcription start sites [29]. Together, these and other studies demonstrate that LOH in cancer genomes is not only affecting tumor suppressor genes but also numerous non-driver genes.…”

“…In general, there are two types of LOH, (1) LOH with copy number losses (CNL-LOH), with a typical example of being losing the wildtype allele of a tumor suppressor, and (2) copy number neutral LOH (CNN-LOH), exemplified by the presence of two mutant alleles of WT1 (11p), FLT3 (13q), CEBPA (19q) and RUNX1 (21q) which resulted in a growth advantage in tumors, such as in leukemia [3]. A complete or partial deletion of a chromosome leads to CNL-LOH, while CNN-LOH is mainly caused by acquired uniparental disomy (UPD) and gene conversion, and occurs without net change in the copy number [4,5] (Figure 1). In principle, the presence of two mutant alleles generated by CNN-LOH could lead to an alteration at the gene expression level, however, it has been recently shown that there are allelic differences in gene expression [6], indicating that the exact expression level could be associated with specific gene expression patterns and regulated by other mechanisms.…”