Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

Schaid, Daniel J.; McDonnell, Shannon K.; FitzGerald, Liesel M.; DeRycke, Lissa; Fogarty, Zachary C.; Giles, Graham G.; MacInnis, Robert J.; Southey, Melissa C.; Nguyen-Dumont, Tú; Cancel‐Tassin, Géraldine; Cussenot, Olivier; Whittemore, Alice S.; Sieh, Weiva; Ioannidis, Nilah M.; Hsieh, Chih Lin; Stanford, Janet L.; Schleutker, Johanna; Cropp, Cheryl D.; Carpten, John D.; Hoegel, Josef; Eeles, Rosalind; Kóte-Jarai, Zsofia; Ackerman, Michael J.; Klein, Christopher J.; Mandal, Diptasri; Cooney, Kathleen A.; Bailey-Wilson, Joan E.; Helfand, Brian T.; Catàlona, William J.; Wiklund, Fredrick; Riska, Shaun M.; Bahetti, Saurabh; Larson, Melissa C.; Albright, Lisa Cannon; Teerlink, Craig C.; Xu, Jianfeng; Isaacs, William B.; Ostrander, Elaine A.; Thibodeau, Stephen N.

doi:10.1016/j.eururo.2020.07.038

Cited by 32 publications

(35 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CSF3R is closely related to prognosis of patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia and thus represents a potentially useful criterion for disease diagnosis ( 23 ). QKI gene encodes an RNA-binding protein that regulates the functions of diverse mRNAs, which play critical parts in tumorigenesis through inactivation of tumor suppressor genes in multiple tumors ( 24 , 25 ). LAMP2 is essential for maintaining the structural integrity of the lysosomal compartment and relocalizes to the cell surface of some highly metastatic tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes

Chen

Pei

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumor entity, which makes prognostic prediction challenging. The tumor microenvironment (TME) has a crucial role in fostering and restraining tumor development. Consequently, we performed a systematic investigation of the TME and genetic factors associated with DLBCL to identify prognostic biomarkers for DLBCL. Data for a total of 1,084 DLBCL patients from the Gene Expression Omnibus database were included in this study, and patients were divided into a training group, an internal validation group, and two external validation groups. We calculated the abundance of immune–stromal components of DLBCL and found that they were related to tumor prognosis and progression. Then, differentially expressed genes were obtained based on immune and stromal scores, and prognostic TME‐related genes were further identified using a protein–protein interaction network and univariate Cox regression analysis. These genes were analyzed by the least absolute shrinkage and selection operator Cox regression model to establish a seven-gene signature, comprising TIMP2, QKI, LCP2, LAMP2, ITGAM, CSF3R, and AAK1. The signature was shown to have critical prognostic value in the training and validation sets and was also confirmed to be an independent prognostic factor. Subgroup analysis also indicated the robust prognostic ability of the signature. A nomogram integrating the seven-gene signature and components of the International Prognostic Index was shown to have value for prognostic prediction. Gene set enrichment analysis between risk groups demonstrated that immune-related pathways were enriched in the low-risk group. In conclusion, a novel and reliable TME relevant gene signature was proposed and shown to be capable of predicting the survival of DLBCL patients at high risk of poor survival.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes

Chen

Pei

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Specifically RNASEH2B deletions were reported in 57% of chronic lymphocytic leukemias and 36% of aggressive prostate cancers [28]. Interestingly, an exome sequencing study of 491 cases has proposed RNASEH2B as a candidate gene for prostate cancer [20]. A possible role for ovarian cancer had not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Germline variation of Ribonuclease H2 genes in ovarian cancer patients

et al. 2020

View full text Add to dashboard Cite

Epithelial ovarian carcinoma (EOC) is a genetically heterogeneous disease that is partly driven by molecular defects in mismatch repair (MMR) or homology-directed DNA repair (HDR). Ribonuclease H2 serves to remove mis-incorporated ribonucleotides from DNA which alleviates HDR mechanisms and guides the MMR machinery. Although Ribonuclease H2 has been implicated in cancer, the role of germline variants for ovarian cancer is unknown. In the present case-control study, we sequenced the coding and flanking untranslated regions of the RNASEH2A, RNASEH2B and RNASEH2C genes, encoding all three subunits of Ribonuclease H2, in a total of 602 German patients with EOC and of 940 healthy females from the same population. We identified one patient with a truncating variant in RNASEH2B, p.C44X, resulting in a premature stop codon. This patient had high-grade serous EOC with an 8 years survival after platinum/taxane-based therapy. Subsequent analysis of TCGA data similarly showed a significantly longer progression-free survival in ovarian cancer patients with low RNASEH2B or RNASEH2C expression levels. In conclusion, loss-of-function variants in Ribonuclease H2 genes are not common predisposing factors in ovarian cancer but the possibility that they modulate therapeutic platinum response deserves further investigation.

show abstract

“…The observation that one EZH2 variant carrier was detected per family is likely to be influenced by the WES selection strategy for the PROGRESS study. 11,17 Uncle-nephew and/or cousin pairs were prioritised for WES, and only a small number of individuals were sequenced in each family (minimum two and up to five). Of the six affected variant carriers, four belonged to families where the most closely related genotyped case to the variant carrier were cousins and/or nephews.…”

Section: Ezh2 Variant Association With Prostate Cancer Risk In a Nortmentioning

confidence: 99%

A rare variant in EZH2 is associated with prostate cancer risk

Raspin

FitzGerald

Marthick

et al. 2021

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole-genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10 −5 ).Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild-type cases. Although no allele-dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild-type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top-ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.

show abstract

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

Cited by 32 publications

References 18 publications

Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes

Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes

Germline variation of Ribonuclease H2 genes in ovarian cancer patients

A rare variant in EZH2 is associated with prostate cancer risk

Contact Info

Product

Resources

About