Are there any more ovarian tumor suppressor genes? A new perspective using ultra high‐resolution copy number and loss of heterozygosity analysis

Abstract

Ovarian cancer is characterized by complex genetic alterations, including copy number loss and copy number-neutral loss of heterozygosity (LOH). These alterations are assumed to represent the "second hit" of the underlying tumor suppressor gene (TSG), however, relative to the number of LOH hotspots reported, few ovarian TSGs have been identified. We conducted a high-resolution LOH analysis using SNP arrays (500K and SNP6.0) of 106 primary ovarian tumors of various histological subtypes together with matching normal DNA. LOH was detected in at least 35% of samples on chromosomes 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, 1p, 16q, and 9q with a median minimal region of overlap of only 300 kb. Subtype-specific differences in LOH frequency were noted, particularly for mucinous cases. We also identified 192 somatic homozygous deletions (HDs). Recurrent HDs targeted known TSGs such as CDKN2A (eight samples), RB1 (five samples), and PTEN (three samples). Additional recurrent HDs targeted 16 candidate TSGs near minimal regions of LOH on chromosomes 17, 13, 8p, 5q, and X. Given the importance of HDs in inactivating known genes, these candidates are highly likely to be ovarian TSGs. Our data suggest that the poor success of previous LOH studies was due to the inability of previous technology to resolve complex genomic alterations and distinguish true LOH from allelic imbalance. This study shows that recurrent regions of LOH and HD frequently align with known TSGs suggesting that LOH analysis remains a valid approach to discovering new candidates.

Epigenetic regulation of IQGAP2 promotes ovarian cancer progression via activating Wnt/β-catenin signaling

“…Among those altered genes, IQGAP2 is hypermethylated and its expression is decreased in ovarian cancers. Indeed, loss of heterozygosity of IQGAP2 is reported in ovarian cancer (22). Hypermethylation of IQGAP2 is also observed in gastric cancer (10).…”

Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma

“…Deletion of 19p is also a common event in many other cancers including lung cancer (13), hepatocellular carcinoma (14), and ovarian cancer (15), suggesting the existence of multiple TSGs on 19p. In esophageal cancer, chromosome 19p13.3 is a frequently deleted region.…”

Genome Wide DNA Copy Number Analysis of Serous Type Ovarian Carcinomas Identifies Genetic Markers Predictive of Clinical Outcome

“…Several expression profiling based studies have identified gene expression signatures associated with response to chemotherapy [22], [23] and to different subtypes of ovarian cancer [21], [24]. High-level amplifications of ERBB2 , MYC , PIK3CA , EVI1 , RAB25 , AKT2 , CCNE1 , NOTCH3 , FGFR2 , CCND1 , PAK1 , EMSY , ZNF217 , NCOA3 [23], [25], [26], [27], [28], [29], [30], [31], [32] and homozygous deletion, mutation, reduced expression and/or hypermethylation of TP53 , KRAS , LOT1 , DOC2 , NOEY2 , OVCA1 , SPARC , CDKN2A , RB1 , PTEN [33], [34], [35], [36], [37], [38], [39] genes have also been reported. However, little consensus or overlap between all these studies has emerged.…”