31 research outputs found
Abstract 1287: Multigene panel testing and risk estimates in 10,233 ovarian cancer cases
No full textAbstract
Germline pathogenic variants in BRCA1 and BRCA2 account for 10% of ovarian cancer (OC), including ovarian, fallopian tube, and primary peritoneal carcinomas. Pathogenic variants in BRIP1, RAD51C, RAD51D, and other cancer predisposition genes have been observed in another 2% to 5% of OCs. However, the specific genes associated with OC and estimates of risk associated with pathogenic variants in the individual genes are not well defined. We sought to determine the relevance of multigene panel testing results for OC cases. The study was focused on 140,449 individuals, including 10,233 OC cases, receiving clinical panel testing of cancer predisposition genes. Standardized relative risks (SRR) for pathogenic variants in 18 cancer predisposition genes were estimated using reference controls from the Exome Aggregation Consortium (ExAC). The median (range) age at diagnosis of OC was 57 (21-90) years. OC cases were 76.2% Caucasian, 3.6% African American, 4.6% Asian, 4.7% Hispanic, and 10.9% unknown/other. Among the 10,233 OC cases, 1391 (13.6%) had pathogenic mutations, including 1032 pathogenic mutations among the 7793 Caucasian OC cases (13.2%). Using the non-Finnish European ExAC (excluding TCGA samples) reference controls, the allele frequency for all pathogenic variants in each gene was summed and compared to the frequency of mutations in the Caucasian OC cases. Pathogenic variants in the known OC predisposition genes: BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, and RAD51D were associated with a high risk of OC (SRR>4.0). Additionally, significant associations were observed for pathogenic variants in suspected OC risk genes ATM and PALB2 (SRR=2.06 and 2.78, respectively). This study identified several genes routinely screened on multigene panel testing that confer high or moderate risks of OC. Associations with known OC predisposition genes were confirmed. In addition, this study provides evidence that PALB2 is a moderate risk OC gene, and that ATM may confer lower to moderate risks of OC. If confirmed in future studies, these risks should be carefully considered in future screening and management of OC patients. In contrast, BARD1 and genes in the MRN complex were not associated with clinically relevant risks of OC.
Citation Format: Jenna Lilyquist, Holly LaDuca, Eric Polley, Hermela Shimelis, Chunling Hu, Raymond Moore, Steven N. Hart, Fergus J. Couch, Jill Dolinsky, David E. Goldgar. Multigene panel testing and risk estimates in 10,233 ovarian cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1287. doi:10.1158/1538-7445.AM2017-1287</jats:p
Abstract 3406: Hereditary risks of male breast cancer in a multi-gene panel testing cohort
No full textAbstract
While the population-based risk for breast cancer in males remains relatively low (1:1000), inherited predisposition can significantly raise this to as high as 10%, in men who carry a mutation in the BRCA2 gene. Lifetime breast cancer risks of 1-2% have also been reported in men who carry a mutation in BRCA1. These risks, as well as elevated risks of prostate, pancreatic, and melanoma cancers, are important to discuss in families diagnosed with Hereditary Breast and Ovarian Cancer Syndrome, which is often viewed as being clinically relevant only to the women in an affected family. However, beyond the BRCA1/2 genes, limited data is available on hereditary predisposition to male breast cancer. We analyzed clinical histories and molecular results from multi-gene panel testing for hereditary cancer predisposition in a cohort of 715 men affected by breast cancer. A total of 708 male breast cancer patients were eligible for inclusion in the final analysis. Molecular testing included analysis of 5 to 59 genes for DNA coding sequence and copy number variants by next-generation sequencing and microarray. Genetic variants identified were classified according to a 5-tier system using previously validated algorithms1,2. Only those variants classified as pathogenic or likely pathogenic were included in the analyses as positive for a mutation. Overall, a mutation was detected in 18% of these men. Four subjects carried a mutation in two different breast cancer predisposition genes. BRCA2 and CHEK2 were the most frequently mutated genes. The risk of breast cancer was significantly elevated compared to public controls in individuals with a mutation in BRCA2 (odds ratio (OR)=13.9; p=1.92x10-16), CHEK2 (OR=3.8; p=6.24x10-24) and PALB2 (OR=6.6, p=0.01). Average age was similar amongst men with (63.5±2.7 years) and without (62.3±1.2 years) mutations, as were clinical and family histories of additional cancers. The high overall diagnostic yield suggests the utility of testing all male breast cancer patient regardless of age or family history by multigene panel testing, and provides data to support risk-based counseling and medical recommendations for screening and/or prevention in male mutation carriers.
1. 1. LaDuca et al. Genet Med. 2014 Nov;16(11):830-7 2. 2. Richards et al. Genet Med. 2015 May;17(5):405-24
Citation Format: Elizabeth C. Chao, Mary Pritzlaff, Summerour Pia, Rachel McFarland, Shuwei Li, Jill Dolinsky, David Goldgar, Hermela Shimelis, Fergus Couch, LaDuca Holly. Hereditary risks of male breast cancer in a multi-gene panel testing cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3406. doi:10.1158/1538-7445.AM2017-3406</jats:p
Abstract 4286: What have we learned from pancreatic cancer patients undergoing multigene panel testing
No full textAbstract
Purpose: The relevance of inherited pathogenic variants in cancer predisposition genes to pancreatic cancer (PC) is not well understood. Several small studies have identified pathogenic variants in 4% to 14% of unselected PC patients using multigene panels of predisposition genes, but only BRCA2, ATM, and PALB2 have been clearly implicated in this disease. We aimed to assess the clinical and molecular characteristics of PC patients referred for hereditary cancer genetic testing, and to estimate the risk of PC associated with pathogenic variants in panel-based cancer predisposition genes.
Methods: PC patients (n=1,819) were ascertained from a large cohort of over 140,000 patients undergoing multigene panel testing (MGPT) of predisposition genes between March 2012 and June 2016 at a single diagnostic laboratory. Clinical histories and molecular results were reviewed and summarized. Gene-level variant frequencies among PC cases were compared to those from the Exome Aggregation Consortium (ExAC) to calculate gene-specific pancreatic cancer risk ratios.
Results: PC patients were predominantly Caucasian (76.5%) and female (58.9%), with a median age at diagnosis of 61 years (51.7). Of these, 33.5% reported additional cancer primaries, and 44.8% reported a family history of PC. Overall, 15.4% of PC patients were found to have at least one pathogenic/likely pathogenic variant in panel-based predisposition genes. Genes with the highest frequencies of pathogenic/likely pathogenic variants included BRCA2 (3.9%), ATM (3.6%), CHEK2 (excluding p.Ile157Thr) (2.0%), PALB2 (1.5%), VHL (1.4%), CDKN2A (1.2%), BRCA1 (0.8%), and MSH6 (0.8%). 21.8% of BRCA1 and BRCA2 carriers did not meet BRCA1/2 testing criteria and 61.5% of MSH6 carriers did not meet Lynch syndrome testing criteria. No CDKN2A families met diagnostic criteria for familial atypical multiple mole melanoma syndrome, and 44% did not report any personal or family history of melanoma. To estimate associations between pathogenic variants and pancreatic cancer, Caucasian PC cases were compared to non-Finnish European, non-TCGA ExAC reference controls. Pathogenic variants in ATM, BRCA2, CDKN2A, MSH6, and PALB2 were significantly associated with high PC risks. Pathogenic variants in BRCA1 were associated with a moderate risk of PC (RR=2.7).
Conclusions: These findings shed light on the spectrum of mutations that can be expected for PC patients referred for cancer predisposition testing. The results confirm the associations of CDKN2A and BRCA2 variants with PC, and expand on the phenotypic spectrum associated with these variants. Furthermore, these results suggest that ATM, PALB2, and MSH6 may be high-risk PC genes, warranting further investigation in case-control and family-based studies.
Citation Format: Holly LaDuca, Chunling Hu, Hermela Shimelis, Eric Polley, Jenna Lilyquist, Mary Helen Black, Brigette Tippin Davis, David E. Goldgar, Jill Dolinsky, Fergus J. Couch. What have we learned from pancreatic cancer patients undergoing multigene panel testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2017-4286</jats:p
Regulation of p27 (Kip1) by Ubiquitin E3 Ligase RNF6
No full textThe cyclin-dependent kinase inhibitor p27 (Kip1) is an important regulator of the G1/S checkpoint. It is degraded by the SCF-SKP2 complex in late G1 thereby allowing cells to progress to the S phase. Here we investigated the role of the E3 ubiquitin ligase RNF6 (Ring Finger Protein 6) in cell cycle progression in prostate cancer cells. Our data demonstrate that RNF6 can promote cell cycle progression by reducing the levels of p27. Knockdown of RNF6 led to an increase in the stability of p27 and to the arrest of cells in the G1 phase. RNF6 interacted with p27 via its KIL domain and this interaction was found to be phosphorylation independent. RNF6 enhanced ubiquitination and subsequent degradation of p27 in the early G0/G1 phase of the cell cycle. Knockdown of RNF6 expression by short hairpin RNA led to inhibition of the CDK2/Cyclin E complex thereby reducing phosphorylation of Retinoblastoma protein (Rb) and to a subsequent decrease in cell cycle progression and proliferation. Our data suggest that RNF6 acts as a negative regulator for p27kip1 leading to its proteasome-dependent degradation in the early G0/G1 phase of the cell cycle
Abstract 4685: Characterization of variants of uncertain significance (VUS) in breast and ovarian cancer predisposition genes
No full textTriple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing
Get PDFBackground: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.</p
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls
No full textAbstract 4089: Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases.
No full textNovel Membrane-associated Androgen Receptor Splice Variant Potentiates Proliferative and Survival Responses in Prostate Cancer Cells
Get PDFProgression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors
