Discovery of rare coding variants in <i>OGDHL</i> and <i>BRCA2</i> in relation to breast cancer risk in Chinese women

Guo, Xingyi; Long, Jirong; Chen, Zhishan; Shu, Xiao‐Ou; Xiang, Yong‐Bing; Wen, Wanqing; Zeng, Chenjie; Gao, Yu‐Tang; Cai, Qiuyin; Wang, Zheng

doi:10.1002/ijc.32825

Cited by 10 publications

(5 citation statements)

References 39 publications

(86 reference statements)

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“…Gene-expression and whole-genome sequencing data from these samples were processed according to the GTEx protocol, as described in our previous work. [39][40][41] For gene-expression data, expression levels of each gene have been measured using reads per kilobase per million units from RNA-SeQC. We performed data quality control and normalization processing by filtering lowly expressed genes, log2 transforming, and Robust Multichip Average.…”

Section: Gene-expression Model Building Using Genotype-tissue Expressionmentioning

confidence: 99%

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Guo¹,

Lin²,

Wen³

et al. 2021

Gastroenterology

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See Covering the Cover synopsis on page 976. BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n ¼ 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dualluciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferronicorrected threshold of P < 9.1 Â 10 -6 , including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

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Section: Gene-expression Model Building Using Genotype-tissue Expressionmentioning

confidence: 99%

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Guo¹,

Lin²,

Wen³

et al. 2021

Gastroenterology

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“…The median sequence read depth was − 50X. The processing of the sequencing data has been previously described [23][24][25]. Briefly, paired-end reads were aligned to the human genome reference hg19 using BWA (version 0.75).…”

Section: Whole-exome Sequencing and Quality Controlmentioning

confidence: 99%

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women

Zeng

Wen

Shi

et al. 2020

Breast Cancer Res Treat

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Purpose Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case-control study conducted in Shanghai, China. Methods We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study. Results Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10 −15). Among cases, 3.7% had a BRCA 2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA 1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants. Conclusions This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.

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“…OGDHL overexpression and knockdown studies have shown that OGDHL inhibits cell growth and migration by inactivating ATK signaling 56 . Moreover, a recent study revealed that rare variants of OGDHL were significantly correlated with breast cancer in a Chinese cohort 57 , and its association with parathyroid carcinoma is also worth considering. Second, carcinoma-specific gene expression or repression suggests the underlying molecular mechanisms of tumor progression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Genomic and transcriptomic profiling reveal molecular characteristics of parathyroid carcinoma

Hong

Lee

et al. 2023

Exp Mol Med

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Genomic and transcriptomic profiling has enhanced the diagnostic and treatment options for many cancers. However, the molecular characteristics of parathyroid cancer remain largely unexplored, thereby limiting the development of new therapeutic interventions. Herein, we conducted genomic and transcriptomic sequencing of 50 parathyroid tissues (12 carcinomas, 28 adenomas, and 10 normal tissues) to investigate the intrinsic and comparative molecular features of parathyroid carcinoma. We confirmed multiple two-hit mutation patterns in cell division cycle 73 (CDC73) that converged to biallelic inactivation, calling into question the presence of a second hit in other genes. In addition, allele-specific repression of CDC73 in copies with germline-truncating variants suggested selective pressure prior to tumorigenesis. Transcriptomic analysis identified upregulation of the expression of E2F targets, KRAS and TNF-alpha signaling, and epithelial-mesenchymal transition pathways in carcinomas compared to adenomas and normal tissues. A molecular classification model based on carcinoma-specific genes clearly separated carcinomas from adenomas and normal tissues, the clinical utility of which was demonstrated in two patients with uncertain malignant potential. A deeper analysis of gene expression and functional prediction suggested that Wilms tumor 1 (WT1) is a potential biomarker for CDC73-mutant parathyroid carcinoma, which was further validated through immunohistochemistry. Overall, our study revealed the genomic and transcriptomic profiles of parathyroid carcinoma and may help direct future precision diagnostic and therapeutic improvements.

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Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women

Cited by 10 publications

References 39 publications

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women

Genomic and transcriptomic profiling reveal molecular characteristics of parathyroid carcinoma

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