Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas.

Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism analysis with 57 epithelial ovarian cancers (31 CCCs, 14 SCs, and 12 ECs) and microarray expression analysis with 55 cancers (25 CCCs, 16 SCs, and 14 ECs). We then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%; P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the CCC-1 and CCC-3 clusters (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%; P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis

Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas

金沢大学医薬保健研究域医学系Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism analysis with 57 epithelial ovarian cancers (31 CCCs, 14 SCs, and 12 ECs) and microarray expression analysis with 55 cancers (25 CCCs, 16 SCs, and 14 ECs). We then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%; P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the CCC-1 and CCC-3 clusters (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%; P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis. © 2015 Uehara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Correction: Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas

金沢大学医薬保健研究域医学系Correction to: PLoS ONE https://journals.plos.org/plosone/article?id=10.1371/journal.pone.012806

SNP profiling discriminates histology-related subgroups based on chromosomal instability status.

<p>Chromosomal instability status (CIN) according to the number of allele-specific copy number alterations (CNAs) and copy number neutral loss of heterozygosity (CNN LOH), using a human mapping 250K single nucleotide polymorphism (SNP) array with paired tumor DNA and normal DNA. CNAs were divided into three subgroups: CIN-high (≥9 arms with CNAs), CIN-low (1–8 arms with CNAs), and CIN-negative (0 CNAs). (A) Details of number of chromosomal arms with CNAs in each tumor of three histological subtypes (serous carcinomas, SC; clear cell carcinomas, CCC; endometrioid carcinomas, EC). Stage I/II and stage III/IV are colored differently. (B) Correlation between CIN status and histological subtypes. (C) Overview of CNAs by running SNP arrays with 57 ovarian cancer samples. Hierarchical clustering based on the Euclidean distance for dissimilarities is shown. The type A cluster includes tumors with a broad range and low frequency of CNAs, whereas the type B cluster includes tumors with a focal range and high frequency of CNAs. C, E, and S indicate clear cell carcinoma, endometrioid carcinoma, and serous carcinoma, respectively.</p

Integrated analyses reveal a poor-prognostic clear cell signature associated with high chromosomal instability.

<p>Comparison of clear cell carcinoma (CCC) clusters CCC-1 and CCC-2 by gene expression profiling. (A) <i>UGT1A6</i> and <i>UGT1A10</i> were significantly upregulated in CCC-1 compared with CCC-2. (B) The cluster of genes upregulated in CCC-1 compared with CCC-2. The cluster includes <i>STAT3</i> and <i>HIF2A</i>.</p

Ratio of whole arm CNAs among all the CNAs in serous and clear cell carcinomas.

<p>Ratio of whole arm CNAs among all the CNAs in serous and clear cell carcinomas.</p

Correlation between clustering by expression arrays, genetic alterations and clinicopathological characteristics in CCC.

<p>Sensitive*: Complete response or Partial response.</p><p>Resistant**: Stable disease or Progressive disease.</p><p>Correlation between clustering by expression arrays, genetic alterations and clinicopathological characteristics in CCC.</p

Clustering by expression arrays and clinicopathological characteristics.

<p>Sensitive*: Complete response or Partial response.</p><p>Resistant**: Stable disease or Progressive disease.</p><p>p-value (by Fisher's exact test).</p><p>Clustering by expression arrays and clinicopathological characteristics.</p