Gene Summary

Gene:POLL; DNA polymerase lambda
Summary:This gene encodes a DNA polymerase. DNA polymerases catalyze DNA-template-directed extension of the 3'-end of a DNA strand. This particular polymerase, which is a member of the X family of DNA polymerases, likely plays a role in non-homologous end joining and other DNA repair processes. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA polymerase lambda
Source:NCBIAccessed: 14 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: POLL (cancer-related)

Svenson S, Case RI, Cole RO, et al.
Tumor Selective Silencing Using an RNAi-Conjugated Polymeric Nanopharmaceutical.
Mol Pharm. 2016; 13(3):737-47 [PubMed] Related Publications
Small interfering RNA (siRNA) therapeutics have potential advantages over traditional small molecule drugs such as high specificity and the ability to inhibit otherwise "undruggable" targets. However, siRNAs have short plasma half-lives in vivo, can induce a cytokine response, and show poor cellular uptake. Formulating siRNA into nanoparticles offers two advantages: enhanced siRNA stability against nuclease degradation beyond what chemical modification alone can provide; and improved site-specific delivery that takes advantage of the enhanced permeability and retention (EPR) effect. Existing delivery systems generally suffer from poor delivery to tumors. Here we describe the formation and biological activity of polymeric nanopharmaceuticals (PNPs) based on biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) conjugated to siRNA via an intracellular cleavable disulfide linker (PLGA-siRNA). Additionally, these PNPs contain (1) PLGA conjugated to polyethylene glycol (PEG) for enhanced pharmacokinetics of the nanocarrier; (2) a cation for complexation of siRNA and charge compensation to avoid high negative zeta potential; and (3) neutral poly(vinyl alcohol) (PVA) to stabilize the PNPs and support the PEG shell to prevent particle aggregation and protein adsorption. The biological data demonstrate that these PNPs achieve prolonged circulation, tumor accumulation that is uniform throughout the tumor, and prolonged tumor-specific knockdown. PNPs employed in this study had no effect on body weight, blood cell count, serum chemistry, or cytokine response at doses >10 times the effective dose. PNPs, therefore, constitute a promising solution for achieving durable siRNA delivery and gene silencing in tumors.

Nikitina D, Chen Z, Vallis K, et al.
Relationship between Caffeine and Levels of DNA Repair and Oxidative Stress in Women with and without a BRCA1 Mutation.
J Nutrigenet Nutrigenomics. 2015; 8(4-6):174-84 [PubMed] Related Publications
BACKGROUND: Coffee consumption has been associated with a reduction in breast cancer risk among women with a BRCA1 mutation. The objective of this study was to evaluate whether major contributors of caffeine intake are associated with a reduction in DNA damage and/or oxidative stress in women with and without a BRCA1 mutation.
METHODS: Coffee, tea, soda and total caffeine consumption was collected by a dietary history questionnaire, and DNA repair capacity in lymphocytes was assessed by the comet assay (tail moments), micronucleus test (per 1,000 binucleated cells) and analysis of γ-H2AX staining (nuclear foci). The thiobarbituric acid-malondialdehyde and DTNB assays were used to estimate serum lipid peroxidation (µmol/l) and protein oxidation (µmol/l), respectively.
RESULTS: Among all women, high levels of caffeine and caffeinated coffee intake were associated with significantly lower levels of micronuclei (138.50 vs. 97.67, p = 0.04, and 138.12 vs. 97.70, p = 0.04). There was no significant relationship between caffeine, coffee, tea and soda intake and the other markers of DNA repair capacity and oxidative stress among all women and in analyses stratified by BRCA1 mutation status.
CONCLUSION: The chemopreventive effects of coffee and/or caffeine may be associated with improved capacity to efficiently repair DNA damage.

Lebo PB, Quehenberger F, Kamolz LP, Lumenta DB
The Angelina effect revisited: Exploring a media-related impact on public awareness.
Cancer. 2015; 121(22):3959-64 [PubMed] Related Publications
BACKGROUND: In 2013, Angelina Jolie's double mastectomy and publication of her personal treatment choice for BRCA1 positivity generated considerable media attention. To the authors' knowledge, the current study is the first prospective survey conducted among the general public to measure a quantifiable media-related effect on public awareness.
METHODS: The authors analyzed the changes in the general public's awareness of reconstructive options in breast cancer among 2 female population-matched cohorts aged 18 to 65 years (1000 participants in each cohort) before (March 2013; poll 1) and after (June 2013; poll 2) the announcement of Ms. Jolie's mastectomy in May 2013.
RESULTS: There was an observed increase in public awareness: significantly more women from poll 2 were aware of reconstructive breast surgery being possible after breast cancer-related mastectomy, notably with regard to autologous tissue and single-stage reconstructions. Approximately 20% of the women in poll 2 (205 women) indicated that media coverage regarding Ms. Jolie affected their interest in breast cancer. A question that was exclusive to poll 2 revealed a preference for autologous (66.2%) versus implant-based (8.2%) reconstructions, with the remainder indicating no preference (25.6%). None of the stratification variables were found to be associated with the above findings.
CONCLUSIONS: To the best of the authors' knowledge, this is the first prospective study to demonstrate a statistically significant impact of a celebrity announcement on public awareness regarding breast cancer treatment. The results underscore the importance of a media-related impact for professionals in the health care sector, which can serve as a tipping point for raising awareness and improving knowledge concerning a specific disease among the general public.

Hobbs RP, DePianto DJ, Jacob JT, et al.
Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes.
Nat Genet. 2015; 47(8):933-8 [PubMed] Free Access to Full Article Related Publications
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.

Gao Y, Chen G, Zeng Y, et al.
Invasion and metastasis-related long noncoding RNA expression profiles in hepatocellular carcinoma.
Tumour Biol. 2015; 36(10):7409-22 [PubMed] Related Publications
Recurrence, invasion, and metastasis are the major reasons of the low 5-year survival of hepatocellular carcinoma. However, the mechanisms of recurrence, invasion, and metastasis are still poll understood. Long noncoding RNAs (LncRNAs, >200 nt) have been demonstrated to play important roles in both tumor suppressive and oncogenic signaling pathways. Here, we employed the LncRNAs microarray technology to study the LncRNAs expression profiles at genome-wide in hepatocellular carcinoma (HCC) tissue samples with early recurrence (less than 1 year, with invasion and metastasis out of liver) and late recurrence (longer than 2 years, without invasion and metastasis out of liver), which had different recurrent/metastatic potentials, by using normal liver tissue as control to screen the dysregulated LncRNAs which are potentially involved in the recurrence, invasion, and metastasis process of HCC. Overall, 1170 LncRNAs were identified to differentially expressed between the early and late recurrence samples. These differentially expressed LncRNAs were further characterized by integrating examination of genomic context, co-expression network analysis, and gene ontology (GO) enrichment of their associated protein-coding genes. Furthermore, 15 LncRNAs selected randomly from top 50 differentially expressed LncRNAs were validated by quantitative PCR (qPCR) in cell lines MHCC97H and MHCC97L, which have exactly the same genetic background but with different invasion potentials. Meanwhile, the prognostic potential of three verified LncRNAs at cell line level was further validated in 59 HCC samples. Therefore, our results demonstrated that the aberrant expression of LncRNAs might be responsible for the HCC invasion and metastasis and provide fundamental information for further study the LncRNAs involved molecular mechanisms of the invasion and metastasis of HCC.

Yamanoi K, Arai E, Tian Y, et al.
Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome.
Carcinogenesis. 2015; 36(5):509-20 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome.

Kang S, Savas S, Ozcelik H, Briollais L
Inferring gene network from candidate SNP association studies using a Bayesian graphical model: application to a breast cancer case-control study from ontario.
Hum Hered. 2014; 78(3-4):140-52 [PubMed] Related Publications
BACKGROUND/AIMS: Gene network analysis can be a very valuable approach for elucidating complex dependence between functional SNPs in a candidate genetic pathway and for assessing their association with a disease of interest. Even when the number of SNPs evaluated is relatively small (<20), the number of potential gene networks induced by the SNPs can be very large and the contingency tables representing their joint distribution very sparse.
METHODS: In this paper, we propose a Bayesian model determination for gene network analysis using decomposable discrete graphical models combined with Reversible Jump Markov chain Monte Carlo. We show the application of this approach in a study of 13 SNPs in the DNA repair pathway and their association with breast cancer from a case-control study conducted in Ontario, Canada.
RESULTS: The strength of associations among the SNPs and between the SNPs and the disease status is evaluated by computing the posterior probability of any pair of variables. The corresponding gene network is reconstructed by retaining pair-wise associations with the highest posterior probabilities. In our real data analysis, we found evidence for a particular association between one SNP in the gene POLL and the disease status and also several interesting patterns of association between the SNPs themselves.
CONCLUSION: This general statistical framework could serve as a basis for prioritizing genes and SNPs that play a major role in breast cancer etiology and to better understand their complex interactions in a specific genetic pathway.

Gronwald J, Robidoux A, Kim-Sing C, et al.
Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.
Breast Cancer Res Treat. 2014; 146(2):421-7 [PubMed] Free Access to Full Article Related Publications
Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

Kotsopoulos J, Lubinski J, Moller P, et al.
Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers.
Breast Cancer Res Treat. 2014; 143(3):579-86 [PubMed] Related Publications
It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case-control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20-1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99-1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14-1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03-1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79-1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.

Valentini A, Lubinski J, Byrski T, et al.
The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation.
Breast Cancer Res Treat. 2013; 142(1):177-85 [PubMed] Free Access to Full Article Related Publications
Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan-Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31-1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.

Xu HL, Gao XR, Zhang W, et al.
Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men.
Cancer Epidemiol. 2013; 37(6):917-22 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Translesion DNA synthesis (TLS) plays an important role in promoting replication through DNA lesions. Genetic polymorphisms in TLS genes may have potential roles in lung cancer development in humans.
METHODS: We evaluated the association between genetic variants in six TLS genes and the risk and survival of lung cancer in a case-control study in China. Included in the study are 224 lung cancer patients and 448 healthy controls.
RESULTS: Carriers of the G allele of POLκ rs5744724 had significantly reduced risk of lung cancer (odds ratio (OR)=0.62, 95% confidence interval (CI): 0.44-0.89), comparing with those carrying the C allele, and the AA genotype of PCNA rs25406 was also associated with significantly decreased cancer risk compared with the major homozygote alleles (OR=0.47, 95% CI: 0.25-0.86). Haplotype analysis showed that subjects with the POLκ C-G (rs5744533-rs5744724) haplotype had decreased risk of lung cancer (OR=0.69, 95% CI: 0.49-0.98), comparing with those carrying the C-C haplotype. Besides, the heterozygote of REV1 rs3087386 and rs3792136 were independent prognostic factors for lung cancer survival with hazard radio (HR) 1.54 (95% CI: 1.12-2.12) and 1.44 (95% CI: 1.06-1.97) respectively.
CONCLUSIONS: Our findings suggested that genetic variants in POLκ and PCNA genes may play roles in the susceptibility of lung cancer, and REV1 gene may have roles in lung cancer survival in Chinese men.

Metcalfe KA, Poll A, Royer R, et al.
A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing.
Br J Cancer. 2013; 109(3):777-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Guidelines for genetic testing for BRCA1 or BRCA2 stipulate that a personal or family history of cancer is necessary to be eligible for testing. Approximately 2% of Ashkenazi Jewish women carry a mutation, but to date population-based testing has not been advocated. Little is known about the relative yield of a conventional genetic testing programme versus a programme of widespread testing in a population with common founder mutations.
METHODS: We provided both referral-based and Jewish population-based testing between 2008 and 2012. We compared the numbers of BRCA mutation carriers identified through the two streams and estimated the number of genetic counselling hours devoted to each programme.
RESULTS: From 2008 to 2012, 38 female carriers were identified through 487 referrals to our genetics centre (29 unaffected with cancer). During the same time, 6179 Jewish women were tested through our population-based programme and 93 mutation carriers were identified (92 unaffected with cancer). Fewer counsellor hours were devoted to the population-based than to the clinical referral-based testing programme.
CONCLUSION: Genetic testing of all Jewish women above the age of 25 years will greatly expand the number of BRCA mutation carriers identified without a commensurate increase in the number of hours required for counselling.

Pawlus MR, Hu CJ
Enhanceosomes as integrators of hypoxia inducible factor (HIF) and other transcription factors in the hypoxic transcriptional response.
Cell Signal. 2013; 25(9):1895-903 [PubMed] Free Access to Full Article Related Publications
Hypoxia is a prevalent attribute of the solid tumor microenvironment that promotes the expression of genes through posttranslational modifications and stabilization of alpha subunits (HIF1α and HIF2α) of hypoxia-inducible factors (HIFs). Despite significant similarities, HIF1 (HIF1α/ARNT) and HIF2 (HIF2α/ARNT) activate common as well as unique target genes and exhibit different functions in cancer biology. More surprisingly, accumulating data indicates that the HIF1- and/or HIF2-mediated hypoxia responses can be oncogenic as well as tumor suppressive. While the role of HIF in the hypoxia response is well established, recent data support the concept that HIF is necessary, but not sufficient for the hypoxic response. Other transcription factors that are activated by hypoxia are also required for the HIF-mediated hypoxia response. HIFs, other transcription factors, co-factors and RNA poll II recruited by HIF and other transcription factors form multifactorial enhanceosome complexes on the promoters of HIF target genes to activate hypoxia inducible genes. Importantly, HIF1 or HIF2 requires distinct partners in activating HIF1 or HIF2 target genes. Because HIF enhanceosome formation is required for the gene activation and distinct functions of HIF1 and HIF2 in tumor biology, disruption of the HIF1 or HIF2 specific enhanceosome complex may prove to be a beneficial strategy in tumor treatment in which tumor growth is specifically dependent upon HIF1 or HIF2 activity.

Durando M, Tateishi S, Vaziri C
A non-catalytic role of DNA polymerase η in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks.
Nucleic Acids Res. 2013; 41(5):3079-93 [PubMed] Free Access to Full Article Related Publications
Trans-lesion DNA synthesis (TLS) is a DNA damage-tolerance mechanism that uses low-fidelity DNA polymerases to replicate damaged DNA. The inherited cancer-propensity syndrome xeroderma pigmentosum variant (XPV) results from error-prone TLS of UV-damaged DNA. TLS is initiated when the Rad6/Rad18 complex monoubiquitinates proliferating cell nuclear antigen (PCNA), but the basis for recruitment of Rad18 to PCNA is not completely understood. Here, we show that Rad18 is targeted to PCNA by DNA polymerase eta (Polη), the XPV gene product that is mutated in XPV patients. The C-terminal domain of Polη binds to both Rad18 and PCNA and promotes PCNA monoubiquitination, a function unique to Polη among Y-family TLS polymerases and dissociable from its catalytic activity. Importantly, XPV cells expressing full-length catalytically-inactive Polη exhibit increased recruitment of other error-prone TLS polymerases (Polκ and Polι) after UV irradiation. These results define a novel non-catalytic role for Polη in promoting PCNA monoubiquitination and provide a new potential mechanism for mutagenesis and genome instability in XPV individuals.

Zhou J, Zhang S, Xie L, et al.
Overexpression of DNA polymerase iota (Polι) in esophageal squamous cell carcinoma.
Cancer Sci. 2012; 103(8):1574-9 [PubMed] Related Publications
The present study investigated the transcriptional regulation of low-fidelity translesion DNA synthesis (TLS) polymerases in human esophageal carcinoma. Significantly higher mRNA expression of polymerase zeta (Polξ), RAD18, polymerase iota (Polι), and polymerase kappa (Polκ) was found in esophageal carcinomas. The increased expression of Polι in tumor samples was further confirmed by immunohistochemistry. The promoter of POLI that encodes Polι was found to be hypomethylated, although the overexpression of this gene was unlikely to be associated with methylation in tumors. We further identified Sp1 and Oct-1 binding sites present in the POLI promoter. We observed that the binding affinity of Sp1 to the POLI promoter was significantly increased in cancerous tissues and that Sp1 activated POLI gene transcription in cultured cell lines. The present study demonstrates overexpression of the TLS genes in esophageal carcinoma and identifies a key role for Sp1 in upregulating POLI gene expression.

Metcalfe KA, Mian N, Enmore M, et al.
Long-term follow-up of Jewish women with a BRCA1 and BRCA2 mutation who underwent population genetic screening.
Breast Cancer Res Treat. 2012; 133(2):735-40 [PubMed] Related Publications
There are two mutations in BRCA1 and one in BRCA2, which are present in up to 2.5% of Jewish women. Population genetic testing for Jewish women has been proposed; however, it is unclear how this would impact the uptake of cancer prevention options and psychosocial functioning in women with a positive result. Two thousand and eighty unselected Jewish women were tested for the Jewish BRCA mutations, and 1.1% were positive. Cancer-related distress was measured before testing, and at 1 and 2 years post-testing. Information on uptake of cancer risk reduction options was collected at 2 years. Breast and ovarian cancer risks were estimated using BRCAPRO. Within 2 years of receiving a positive result, 11.1% of women had prophylactic mastectomy, and 89.5% had a prophylactic oophorectomy. The mean breast cancer risk was estimated to be 37.2% at time of testing, compared to 20.9% at 2 years post-testing. The mean ovarian cancer risk was estimated to be 24.5% at time of testing, compared to 7.5% at 2 years following testing. Distress decreased between 1 and 2 years for women with prophylactic mastectomy and oophorectomy (P = 0.02), and for women with prophylactic oophorectomy only (P = 0.04) but not for those with neither surgery. The majority of Jewish women with a BRCA mutation identified through a population screening elected prophylactic oophorectomy, but a few had a prophylactic mastectomy. Uptake of either surgery resulted in decreased distress. Provision of population BRCA testing resulted in reduced risks of breast and ovarian cancers in women with a mutation.

Haroun I, Graham T, Poll A, et al.
Reasons for risk-reducing mastectomy versus MRI-screening in a cohort of women at high hereditary risk of breast cancer.
Breast. 2011; 20(3):254-8 [PubMed] Related Publications
OBJECTIVE: To determine the reasons that motivate women in a cohort of women under intensive surveillance for breast cancer to undergo risk-reducing mastectomy (RRM).
PATIENTS AND METHODS: Women with a BRCA1 or BRCA2 mutation who were enrolled in an MRI-based breast screening study were eligible to participate in this survey. A self-administered questionnaire was given to women who did, and who did not terminate annual MRI-based surveillance in order to undergo RRM. The questionnaire included information on family history, risk perception and satisfaction with screening. In addition, women were asked to provide the principal reason for their choice of having preventive surgery or not, and were asked about their satisfaction with this choice.
RESULTS: 246 women without breast cancer participated in the study. Of these, 39 women (16%) elected to have RRM at some point after initiating screening. Although women who had a mother or sister with breast cancer were more likely to opt for RRM than were women with no affected first-degree relative (21% versus 10%) this did not reach statistical significance. Women who perceived their breast cancer risk to be greater than 50% were more likely to opt for RRM than were women who estimated their risk to be less than 50% (19% versus 6%). Fear of cancer was the most common reason cited for choosing to have RRM (38% of respondents) followed by having had a previous cancer, (25%), then concern over their children (16%).
CONCLUSION: Among women with a BRCA mutation who are enrolled in an MRI-based screening program, a high perception of personal breast cancer risk and a history of breast cancer in a first-degree relative are predictors of the decision to have RRM.

Metcalfe KA, Poll A, Llacuachaqui M, et al.
Patient satisfaction and cancer-related distress among unselected Jewish women undergoing genetic testing for BRCA1 and BRCA2.
Clin Genet. 2010; 78(5):411-7 [PubMed] Related Publications
It is not known to what extent participation in a genetic testing program for BRCA1 and BRCA2, which does not include an extensive pre-test counselling session, influences cancer-related distress, cancer risk perception and patient satisfaction. Unselected Jewish women in Ontario were offered genetic testing for three common Jewish BRCA mutations. Before testing and 1-year post-testing, the women completed questionnaires which assessed cancer-related distress, cancer risk perception, and satisfaction. A total of 2080 women enrolled in the study; of these, 1516 (73%) completed a 1-year follow-up questionnaire. In women with a BRCA mutation, the mean breast cancer risk perception increased from 41.1% to 59.6% after receiving a positive genetic test result (p = 0.002). Among non-carriers, breast cancer risk perception decreased slightly, from 35.8% to 33.5% (p = 0.08). The mean level of cancer-related distress increased significantly for women with a BRCA mutation, but did not change in women without a mutation; 92.8% expressed satisfaction with the testing process. The results of this study suggest that the majority of Jewish women who took part in population genetic screening for BRCA1 and BRCA2 were satisfied with the delivery of genetic testing and would recommend testing to other Jewish women. However, women with a BRCA mutation experienced increased levels of cancer-related distress.

Metcalfe KA, Poll A, Royer R, et al.
Screening for founder mutations in BRCA1 and BRCA2 in unselected Jewish women.
J Clin Oncol. 2010; 28(3):387-91 [PubMed] Related Publications
PURPOSE: There are two mutations in BRCA1 and one mutation in BRCA2 that are present in up to 2.5% of Ashkenazi Jewish women. Current guidelines for testing stipulate that a personal or family history of cancer be present to be eligible for testing. To date, population screening in this population has not been suggested. However, this may be rational. Little is known about the appropriateness of testing guidelines for the Jewish population or the level of interest in testing.
METHODS: Eligible subjects were women who self-identified as Jewish, who were between the ages of 25 and 80 years, and who resided in Ontario. Subjects were recruited through an article in a national newspaper. Women were asked to complete a study questionnaire and a family history questionnaire and to provide a blood or saliva sample. The risk of carrying a BRCA mutation was estimated for each woman. Results A total of 2,080 women were enrolled onto the study. The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate of carrying a BRCA mutation was 3.9%. Ten (45%) of the 22 women met the current Ontario Ministry of Health Guidelines criteria for testing.
CONCLUSION: There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.

Panchal S, Bordeleau L, Poll A, et al.
Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation-positive families?
Clin Genet. 2010; 77(3):273-9 [PubMed] Related Publications
Women who carry BRCA mutations are advised to begin breast cancer screening based on the age-specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario-based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.

Kotsopoulos J, Shen H, Rao AV, et al.
A BRCA1 mutation is not associated with increased indicators of oxidative stress.
Clin Breast Cancer. 2008; 8(6):506-10 [PubMed] Related Publications
BACKGROUND: Several functions have been attributed to the BRCA1 protein. A recent study suggests that BRCA1 is involved in the cellular antioxidant response by inducing the expression of genes involved in the antioxidant defense system and thus conferring resistance to oxidative stress. It is possible that individuals with a BRCA1 mutation might be susceptible to the effects of oxidative stress. The aim of this study was to evaluate whether women with a BRCA1 mutation exhibit increased indicators of oxidative stress.
PATIENTS AND METHODS: We measured 3 markers of oxidative stress in vivo, the amounts of serum malondialdehyde and protein thiols, and 8-oxo-2'-deoxyguanosine (8-oxodG) levels in 25 unaffected BRCA1 mutation carriers and 25 noncarrier control subjects.
RESULTS: There was no significant difference in serum malondialdehyde levels (P=.41), serum thiol levels (P=.85), or the number of 8-oxodG lesions (P=.49) in BRCA1 mutation carriers versus noncarriers.
CONCLUSION: The results of this study suggest that the presence of a heterozygous BRCA1 mutation is not associated with increased levels of indicators of oxidative stress in serum or lymphocytes. Future studies are warranted to evaluate whether strategies aimed at minimizing oxidative stress might aid in the prevention of hereditary breast cancer.

Narod SA, Neuhausen S, Vichodez G, et al.
Rapid progression of prostate cancer in men with a BRCA2 mutation.
Br J Cancer. 2008; 99(2):371-4 [PubMed] Free Access to Full Article Related Publications
Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation.

van Poll D, Parekkadan B, Cho CH, et al.
Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo.
Hepatology. 2008; 47(5):1634-43 [PubMed] Related Publications
UNLABELLED: Orthotopic liver transplantation is the only proven effective treatment for fulminant hepatic failure (FHF), but its use is limited because of organ donor shortage, associated high costs, and the requirement for lifelong immunosuppression. FHF is usually accompanied by massive hepatocellular death with compensatory liver regeneration that fails to meet the cellular losses. Therefore, therapy aimed at inhibiting cell death and stimulating endogenous repair pathways could offer major benefits in the treatment of FHF. Recent studies have demonstrated that mesenchymal stem cell (MSC) therapy can prevent parenchymal cell loss and promote tissue repair in models of myocardial infarction, acute kidney failure, and stroke through the action of trophic secreted molecules. In this study, we investigated whether MSC therapy can protect the acutely injured liver and stimulate regeneration. In a D-galactosamine-induced rat model of acute liver injury, we show that systemic infusion of MSC-conditioned medium (MSC-CM) provides a significant survival benefit and prevents the release of liver injury biomarkers. Furthermore, MSC-CM therapy resulted in a 90% reduction of apoptotic hepatocellular death and a three-fold increment in the number of proliferating hepatocytes. This was accompanied by a dramatic increase in the expression levels of 10 genes known to be up-regulated during hepatocyte replication. Direct antiapoptotic and promitotic effects of MSC-CM on hepatocytes were demonstrated using in vitro assays.
CONCLUSION: These data provide the first clear evidence that MSC-CM therapy provides trophic support to the injured liver by inhibiting hepatocellular death and stimulating regeneration, potentially creating new avenues for the treatment of FHF.

Nahmias Y, Goldwasser J, Casali M, et al.
Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin.
Hepatology. 2008; 47(5):1437-45 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Hepatitis C virus (HCV) infects over 3% of the world population and is the leading cause of chronic liver disease worldwide. HCV has long been known to associate with circulating lipoproteins, and its interactions with the cholesterol and lipid pathways have been recently described. In this work, we demonstrate that HCV is actively secreted by infected cells through a Golgi-dependent mechanism while bound to very low density lipoprotein (vLDL). Silencing apolipoprotein B (ApoB) messenger RNA in infected cells causes a 70% reduction in the secretion of both ApoB-100 and HCV. More importantly, we demonstrate that the grapefruit flavonoid naringenin, previously shown to inhibit vLDL secretion both in vivo and in vitro, inhibits the microsomal triglyceride transfer protein activity as well as the transcription of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and acyl-coenzyme A:cholesterol acyltransferase 2 in infected cells. Stimulation with naringenin reduces HCV secretion in infected cells by 80%. Moreover, we find that naringenin is effective at concentrations that are an order of magnitude below the toxic threshold in primary human hepatocytes and in mice.
CONCLUSION: These results suggest a novel therapeutic approach for the treatment of HCV infection.

Zhang S, Phelan CM, Zhang P, et al.
Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study.
Cancer Res. 2008; 68(7):2154-7 [PubMed] Related Publications
A founder allele in the CHEK2 gene (1100delC) has been associated with an elevated risk of breast cancer. This allele is responsible for the majority of CHEK2-associated breast cancers in women from northern European countries; however, within Europe, it seems to be rare in countries that are close to the Mediterranean. The frequency of the 1100delC allele has not been measured in non-White populations. We measured the frequency of the CHEK2 founder allele in 3,882 breast cancer patients and 8,609 controls from various countries. The allele was not seen among Asian patients (from Pakistan or the Philippines) and was present in 1 of 155 cases from Brazil. Among White women, the allele was present in 1.5% of 825 familial cases of breast cancer and in 0.7% of 1,106 patients with nonfamilial breast cancer. The allele was equally frequent in Jewish and non-Jewish patients. We estimate that the CHEK2 1100delC allele is associated with an odds ratio of 2.6 for breast cancer, which corresponds to a lifetime risk of approximately 24% in Ontario.

Foulkes WD, Ghadirian P, Akbari MR, et al.
Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
Breast Cancer Res. 2007; 9(6):R83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec.
METHODS: We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls.
RESULTS: We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls.
CONCLUSION: We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.

Metcalfe KA, Poll A, O'Connor A, et al.
Development and testing of a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation.
Clin Genet. 2007; 72(3):208-17 [PubMed] Related Publications
For women who carry a mutation in BRCA1 or BRCA2, the risk of breast cancer is up to 87% by the age of 70. There are options available to reduce the risk of breast cancer; however, each option has both risks and benefits, which makes decision making difficult. The objective is to develop and pilot test a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. The decision aid was developed and evaluated in three stages. In the first stage, the decision aid was developed and reviewed by cancer genetics experts. The second stage was a review of the decision aid by women with a BRCA1 or BRCA2 mutation for acceptability and feasibility. The final stage was a pre-test--post-test evaluation of the decision aid. Twenty-one women completed the pre-test questionnaire and 20 completed the post-test questionnaire. After using the decision aid, there was a significant decline in mean decisional conflict scores (p = 0.001), a significant improvement in knowledge scores (p = 0.004), and fewer women uncertain about prophylactic mastectomy (p = 0.003) and prophylactic oophorectomy (p = 0.009). Use of the decision aid decreased decisional conflict to levels suggestive of implementation of a decision. In addition, knowledge levels increased and choice predisposition changed with fewer women being uncertain about each option. This has significant clinical implications as it implies that with greater uptake of cancer prevention options by women with a BRCA1 or BRCA2 mutation, fewer women will develop and/or die of hereditary breast cancer.

Rajpert-De Meyts E, Poll SN, Goukasian I, et al.
Changes in the profile of simple mucin-type O-glycans and polypeptide GalNAc-transferases in human testis and testicular neoplasms are associated with germ cell maturation and tumour differentiation.
Virchows Arch. 2007; 451(4):805-14 [PubMed] Related Publications
Testicular germ cell tumours (TGCT) exhibit remarkable ability to differentiate into virtually all somatic tissue types. In this study, we investigated changes in mucin-type O-glycosylation, which have been associated with somatic cell differentiation and cancer. Expression profile of simple mucin-type O-glycans (Tn, sialyl-Tn, T), histo-blood group H and A variants and six polypeptide GalNAc-transferases (T1-4, T6, T11) that control the site and density of O-glycosylation were analysed by immunohistochemistry during human testis development and in TGCT. Normal testis showed a restricted pattern; gonocytes expressed abundant sialyl-Tn and sialyl-T, and adult spermatogonia were devoid of any glycans, whereas spermatocytes and spermatids expressed exclusively glycans Tn and T and the GalNAc-T3 isoform. A subset of mature ejaculated spermatozoa expressed an additional glycan sialyl-T. The pattern found in testicular neoplasms recapitulated the developmental order: Pre-invasive carcinoma in situ (CIS) cells and seminoma expressed fetal type sialylated glycans in keeping with their gonocyte-like phenotype. Neither simple mucin-type O-glycans nor GalNAc-transferase isoforms were found in undifferentiated nonseminoma, i.e. embryonal carcinoma, whereas teratomas expressed them all to some extent but in a disorganized manner. We concluded that simple mucin-type O-glycans and their transferases are developmentally regulated in the human testis, with profound changes associated with neoplasia. The restricted O-glycosylation pattern in haploid germ cells suggests a role in their maturation or egg recognition/fertilization warranting further studies in male infertility, whereas the findings in TGCT provide new diagnostic tools and support our hypothesis that testicular cancer is a developmental disease of germ cell differentiation.

Tischkowitz M, Xia B, Sabbaghian N, et al.
Analysis of PALB2/FANCN-associated breast cancer families.
Proc Natl Acad Sci U S A. 2007; 104(16):6788-93 [PubMed] Free Access to Full Article Related Publications
No more than approximately 30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.

Kotsopoulos J, Chen Z, Vallis KA, et al.
DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers.
Br J Cancer. 2007; 96(1):118-25 [PubMed] Free Access to Full Article Related Publications
The BRCA1 gene product helps to maintain genomic integrity through its participation in the cellular response to DNA damage: specifically, the repair of double-stranded DNA breaks. An impaired cellular response to DNA damage is a plausible mechanism whereby BRCA1 mutation carriers are at increased risk of breast cancer. Hence, an individual's capacity to repair DNA may serve as a useful biomarker of breast cancer risk. The overall aim of the current study was to identify a biomarker of DNA repair capacity that could distinguish between BRCA1 mutation carriers and non-carriers. DNA repair capacity was assessed using three validated assays: the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of gamma-H2AX nuclear foci. DNA repair capacity of peripheral blood lymphocytes from 25 cancer-free female heterozygous BRCA1 mutation carriers and 25 non-carrier controls was assessed at baseline and following cell exposure to gamma-irradiation (2 Gy). We found no significant differences in the mean tail moment, in the number of micronuclei or in the number of gamma-H2AX nuclear foci between the carriers and non-carriers at baseline, and following gamma-irradiation. These data suggest that these assays are not likely to be useful in the identification of women at a high risk for breast cancer.

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