Association Of Genomic Alterations Research Articles

The association of genomic alterations with PD-L1 expression in Chinese patients with EGFR/ALK wild-type lung adenocarcinoma and potential predictive value of Hippo pathway mutations to immunotherapy.

The study focuses on PD-L1 expression as an essential biomarker for gauging the response of EGFR/ALK wild-type NSCLC patients to FDA-approved immune checkpoint inhibitors (ICIs). It aims to explore clinical, molecular, and immune microenvironment characteristics associated with PD-L1 expression in EGFR/ALK wild-type lung adenocarcinoma patients eligible for ICI therapy. In this retrospective study, tumor samples from 359 Chinese EGFR/ALK wild-type lung adenocarcinoma patients underwent comprehensive evaluations for PD-L1 expression and NGS-targeted sequencing. The investigation encompassed the analysis and comparison of clinical traits, gene mutations, pathways, and immune signatures between two groups categorized by PD-L1 status: negative (TPS < 1%) and positive (TPS ≥ 1%). Additionally, the study explored the link between genomic changes and outcomes following immunotherapy. High tumor mutational burden correlated significantly with PD-L1 positivity in patients with EGFR/ALK wild-type lung adenocarcinoma. Gene alterations, including TP53, KRAS, and others, were more pronounced in the PD-L1 positive group. Pathway analysis highlighted higher frequencies of alterations in pathways like RTK/RAS, p53, and Hippo in PD-L1-positive patients. The Hippo pathway's relevance was confirmed in separate immunotherapy cohorts, associated with better outcomes. In terms of immune cell infiltration, Hippo mutants exhibited higher levels of CD68+ PD-L1+ macrophages, CD8+ T cells, and CD8+ PD-1- T cells. This study offers insights into genomic features of Chinese EGFR/ALK wild-type lung adenocarcinoma patients based on PD-L1 expression. Notably, Hippo pathway alterations were linked to improved immunotherapy outcomes. These findings suggest connections between the Hippo pathway and PD-L1 expression, warranting further clinical and functional investigations. The research advances our understanding of PD-L1 expression's genomic context and immunotherapy response in EGFR/ALK wild-type lung adenocarcinoma.

BIOM-65. SAFE MAXIMAL RESECTION OF IDH-WILDTYPE GLIOBLASTOMA WITH TUMOR-FREE MOLECULAR MARGIN RESULTS IN PROLONGED PROGRESSION-FREE SURVIVAL

Abstract Purpose Although maximal resection of wild-type GBM tumors is associated with longer survival, the association of genomic alterations with the ability to resect disease has not been elucidated. This study aimed to determine whether certain molecular alterations are less amenable to surgical resection and whether achieving a surgical margin devoid of tumor cell burden provides a clinical benefit. Methods Molecular profiling of 148 consecutive tumor samples from newly diagnosed patients with IDH-WT GBM SNaPshot genotyping, and methylation-specific PCR for MGMT promoter methylation. The association of alterations with residual volume and progression-free survival was evaluated in regression analyses. We prospectively investigated the impact of TERTp status at the surgical margin on progression-free survival (PFS) in 47 patients. PFS and overall survival (OS) were evaluated with the log-rank test and Cox regression models.Results Overall, 148 patients (91 men [61.5%], median age, 62.5 years [range 56–70 years] had maximally safe surgery. The median follow-up duration was 18 months (IQR, 4-32 months). The rate of PFS was significantly lower in MGMT promoter unmethylated IDH-WT GBM amenable to resection with residual volume &amp;gt;4.9cc (hazard ratio [HR], 2.35; 95% CI, 1.44-3.84; P=.005). Gene amplification (PDGFRA, KIT, KDR) on 4q12 and TP53 and RB1 mutations were associated with greater RV. Prospective trial revealed median PFS for tumors with TERTp mutations in the surgical margin was 10.1 months while tumors with undetectable TERTp mutations in the margin did not progress (median follow-up 8.1 months, IQR 1.6-14.6). Surgical tumor margins devoid of TERTp mutations were associated with significantly different probability of PFS (0.23; 95%CI 0.15-0.43; P&amp;lt; 0.01)Conclusion In conclusion, 4q12 amplification (KDR/PDGFRA/KIT) and tumor suppressor gene alterations (RB1, TP53) were associated with greater residual volume. Tumor-free margins defined spatially by intraoperative navigation as assessed by quantifying TERTp mutation allelic fraction was correlated with prolonged PFS.

Whole exome sequencing facilitated diagnosis of patients with multiple mucinous neoplasms of the female genital tract.

e17513 Background: The differential diagnosis is challenging in clinical practice, especially among gastric-type AD of the cervix with ovarian metastases, multiple primary mucinous neoplasm in cervix and ovary, and synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT). Previous studies have revealed that next-generation sequencing might be a feasible tool in identifying the origin of tumor. Herein, whole exome sequencing (WES) was performed to distinguish patients with metastatic disease. Methods: WES analysis was performed on 28 tumors and 7 normal tissues derived from 8 patients. Each patient had one lesion of the cervix uteri. Most of them had lesions at other anatomical sites, including corpus uteri, ovary, oviduct, vermiform appendix and omentum. Mutations signatures and clonal evaluation inferred from single-nucleotide/copy number variants were explored. Results: Previous studies of multiple types of cancer have identified more than 40 single-base substitution (SBS) signatures. SBS3/6 referring to defective DNA mismatch repair and SBS10 reported in both uterus and colorectal AD were significantly enriched in this study. Next, we found no significant distribution of SBS3/6/10 among tumors at different anatomical sites. These findings indicate that primary cervical/ovarian AD with metastases other than multiple primary cancers was the predominant histology in 8 patients. The association of genomic alterations in POLE/ POLD1/HRR pathway with the distribution of SBS signatures was explored. SBS3 had a trend of significant distribution (p = 0.01) in four patients who had germline alterations in HRR pathway. Furthermore, SBS10 was significantly enriched (p = 0.009) in 2 patients with germline POLE/POLD1 alterations. Clonal evolution analyses revealed that 2 patients were identified as having SMMN-FGT, and other 6 patients had dominant clones in different tumors, which suggested a . Notably, besides the dominant clones and subclones, some tumors also exhibited extra independent clones, which might be the mixed histology of primary and metastatic tumor. In addition, we found the difference of overall survival in patients having gastric-type AD of the cervix with ovarian metastases and cervical AD patients with different FIGO stage disease based on SEER database data. Conclusions: Our study demonstrated that WES might be a feasible tool to distinguish patients having primary cervical AD with multiple metastases from those with multiple primary cancers of the female genital tract, which suggests that WES proved valuable in facilitating the diagnostic workup. A prospective, multi-center, large cohort study is needed to investigate the performance of WES in identifying the origin of tumors in patients with multiple tumors of the FGT.

Mutation profiling of circulating tumor DNA identifies distinct mutation patterns in non-Hodgkin lymphoma.

Circulating tumor DNA (ctDNA) is emerging as a versatile biomarker for noninvasive genotyping and response monitoring in specific B-cell lymphomas; however, few studies have been conducted to explore ctDNA-based mutation profiling across non-Hodgkin lymphomas (NHLs) and genomic changes after initiation of chemotherapy. A targeted sequencing of 362genes was performed to detect the mutation profiles in paired blood and tissue samples from 42NHL patients. Genomic alterations were explored in 11 diffuse large B-cell lymphoma (DLBCL) patients using paired blood samples collected pre- and post-R-CHOP chemotherapy. The frequencies of PIM1, MYD88, MYC, ZNF292, JAK, and MAF mutations were higher in aggressive than in indolent B-cell lymphoma and NK/T subtypes. Tumor mutation burden in blood samples was higher in aggressive than in indolent B-cell lymphomas and higher in patients who progressed than in those who responded to treatments. Our data also revealed significant enhance of concordance index through integrating mutated genes that were significantly associated with prognosis into International Prognostic Index-based prognostic model. Moreover, acquisition of mutations such as PCLO_p.L1220Tfs*3 was associated with resistance to R-CHOP in DLBCL patients. Our findings illustrated distinct mutation patterns across various NHL subtypes and suggested the association of genomic alterations in ctDNA with treatment outcomes.

CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer.

The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population. Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis. At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non-organ confined. The median PGA was 3.7% (IQR = 0.9%-9.4%) and differed by pathologic grade (P < 0.001) and stage (P = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55-70.86; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2-40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3-35.2; P = 0.026). Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.

Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers

BackgroundImmune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking.MethodsClinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset.ResultsAmong twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (P < 0.001). TET1 was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (n = 519), significant differences were observed between TET1-MUT and TET1-wildtype (TET1-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, P < 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, P < 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], P = 0.008). In the validation cohort (n = 1395), significant overall survival (OS) benefit was detected in the TET1-MUT patients compared to TET1-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], P = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of TET1-MUT (P > 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions.ConclusionsTET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.

Molecular profiling of ER+ metastatic breast cancers to reveal association of genomic alterations with acquired resistance to CDK4/6 inhibitors.

1009 Background: Genomic profiling of ER+ metastatic breast cancer (MBC) has revealed highly prevalent genomic alterations (e.g. ESR1, NF1, ERBB2) associated with exposure to antiestrogen therapy and endocrine resistance. It is not known whether any such acquired genomic alterations are observed after exposure to now standard CDK4/6 inhibitors (CDK4/6i). Methods: To identify genomic alterations associated with acquired resistance to CDK4/6i + antiestrogen combinations, we prospectively performed tumor and matched normal sequencing on 1059 ER+ breast cancers from 845 MBC patients collected prior to (n = 838) or post-treatment with CDK4/6i (n = 221), including 110 pre- and post-treatment pairs. We performed gene enrichment analyses to identify the oncogenic mutations and copy number alterations that were more frequent in post-CDK4/6i samples compared to CDK4/6i-naïve samples and further compared these results to those of post-hormone alone therapy datasets. Results: The post-CDK4/6i samples were collected following exposure to CDK4/6i plus aromatase inhibitors (51%), plus fulvestrant (28%), or multiple/other (21%). Along with alterations previously associated with resistance to hormonal therapy alone, our analysis identified multiple genes to be specifically enriched in the post-CDK4/6i tumors. Among these, loss-of-function alterations in RB1 were significantly enriched in the post-CDK4/6i compared to CDK4/6i-naïve samples (7.9% vs. 2.7%, p-value = 1.5e-5). The majority of the RB1 mutations in the post-CDK4/6i tumors had loss of heterozygosity (LOH), while LOH was uncommon in the CDK4/6i-naive tumors. Additionally, multiple alterations in effectors of PI3K/AKT signaling (excluding PIK3CA), cell cycle (such as CDKN2A loss) and in Hippo signaling were more frequent in the post-CDK4/6i tumors. Conclusions: This large clinico-genomic analysis of the post- and pre-CDK4/6i MBCs reveals multiple genomic lesions to be enriched after exposure to CDK4/6i, highlighting therapy-related genomic evolution as a recurrent phenomenon and identifying unique genomic subsets that have strong potential to alter the benefit of subsequent lines of therapies.

Percent genome alteration and outcomes after radical prostatectomy in African American men.

24 Background: African American (AA) men have a higher incidence of and mortality from prostate cancer (PCa) than European American (EA) men. The potential biological determinants of these racial disparities are unknown. Cancer genome evaluations with available clinical outcome data have been limited to EA cohorts. Here we characterize PCa genomes from a large cohort of AA men and identify the associations between genomic alterations and clinical outcomes. Methods: Cancer genomes from 205 AA men treated with radical prostatectomy (RP) were profiled for known somatic mutations and percent genome alteration (PGA; defined as percentage of tumor genome with copy number variation). Logistic regression and Cox proportional hazard analyses assessed the association of genomic alterations with clinical outcomes in multivariate models. PGA was dichotomized by quartiles in analytical models (≤75th percentile vs. &gt;75th percentile). Results: The median PGA was 3.7% and increased with pathologic grade (p&lt;0.001) and stage (p=0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had significantly worse biochemical recurrence (BCR)-free survival (10 year: 33.5% vs. 50.2%; p=0.006) and metastasis-free survival (10 year: 47.9% vs. 89.0%; p&lt;0.001) than men with lower quartiles of PGA. PGAwas associated with increased risks of higher grade (OR 2.0, 95% CI 1.1-3.7, p=0.03), higher stage (OR 2.0, 95% CI 1.1-3.8, p=0.03), BCR (univariate: HR 1.9, 95% CI 1.2-3.2, p=0.01), and metastasis (HR 9.6, 95% CI 2.9-31.3, p&lt;0.001). The most common somatic mutations were SPOP (12.5%, 123/184), FOXA1 (9.2%, 17/184), and TP53 (4.4%, 8/184). Only TP53 was associated with increased risks of adverse outcomes: higher stage (OR 5.3, 95% CI 1.5-19.4, p=0.01), BCR (univariate: HR 2.4, 95% CI 1.0-5.9, p=0.06), and metastasis (HR 9.5, 95% CI 2.2-40.6, p=0.002). Conclusions: In AA men, PCa genome profiles reveal unique genomic alterations. Notably, PGA in AA men predicts adverse pathologic and oncologic outcomes after RP and can potentially be considered a prognostic biomarker in this racial group. This research highlights the importance of racial ancestry in cancer genomics studies and precision medicine strategies.

Abstract GS1-07: The genomic landscape of 501 metastatic breast cancer patients

Abstract Background: In depth sequencing of primary breast cancer (BC) has identified a heterogeneous repertoire of disease drivers, evidence of clonal evolution and underlying mutational processes. As cancer evolves over time and under treatment pressure, whole genome sequencing (WGS) of metastatic BC (MBC) tissue is crucial to gain further insight into its genetic make-up and driving forces, thereby allowing improved patient management. Methods: Metastatic tissue and matched germline DNA of patients with MBC (N=501) were prospectively recruited under the biopsy protocol of the Center of Personalized Cancer Treatment (CPCT-02; NCT01855477) and analyzed by WGS. Sequence reads were mapped to the reference genome to call somatic single nucleotide variants (SNV), small insertions and deletions (InDels) and copy number variations from which mutational signatures and tumor mutational burden (TMB; the number of SNV and InDels relative to the genome) were derived. The incidence of called aberrations in our cohort was compared to previously reported WGS data of 560 primary BC (BASIS cohort, Nik-Zainal et al. Nature 2016) (Table 1). Results: According to routine diagnostics 303 patients (60.5%) were ER+/HER2-, 70 (14%) triple negative (TNBC), 95 (19%) HER2+ and the remaining 33 (6.6%) had as of yet an unknown subtype. Top 5 recurrently affected genes were TP53 (47%), ATM (33%), MAP2K4 (32%), NCOR1 (31%), ERBB2 (30%). In the metastatic lesions, median TMB was 2.9 per million base pairs (IQR: 1.7-5.3). Interestingly, 53 (11%) patients had a high TMB (≥10). Compared to primary BC (BASIS cohort), we found (subtype-specific) enrichment of alterations in multiple genes such as ATM (0.4% to 33%), GPS2 (1.3% to 29%), MAP2K4 (6.4% to 32%), CBFB (2.7% to 25%), and, as previously reported, ESR1 (1.3% to 20%). APOBEC signature mutations appeared to be enriched in MBC while HRD signature mutations seemed less prevalent. Analyses to reveal additional genomic features is ongoing as well as the association of genomic alterations with uniquely collected information on prior treatments and response to treatment received directly after biopsy (i.e. endocrine therapy alone or combined with CDK4/6 inhibitors and chemotherapy). Also, to exclude methodological bias the raw data of the BASIS cohort will be processed through our pipeline. Table 1:Comparison of ER+/HER2- and TNBC subtypes: BASIS versus CPCT-02 MBC BASISCPCT-02 MBC ER+/HER2-(%)TNBC(%)ER+/HER2-(%)TNBC(%)Number of samples32615530370Median TMB0.962.632.732.91SNV burden/Mbp0.892.52.412.64InDel burden/Mbp0.060.120.210.3Top 5 affected genesPIK3CA (37)TP53 (83)TP53 (43)TP53 (61) TP53 (20)PTEN (37)ATM (43)MYC (37) CCND1 (20)MYC (26)MAP2K4 (37)CDKN2A (33) GATA3 (15)RB1 (24)NCOR1 (35)CDKN2B (33) MYC (14)PIK3CA (17)CDH1 (34)RB1 (33)Mutational signatures (median relative contribution) Age23.27.213.711.8APOBEC6.97.814.68.3Homologous-recombinant deficiency4.439.94.919.8DNA mismatch Repair Deficiency0.600.30 Conclusion: WGS of this unique cohort of patients with MBC shows a genetic make-up roughly similar to primary BC, but does show subtype-specific enrichment of selected driver mutations in metastatic disease. This study provides better insight into the tumor biology of MBC potentially improving management of these patients. Citation Format: Angus L, Wilting SM, van Riet J, Smid M, Steenbruggen TG, Tjan-Heijnen VC, Labots M, van Riel JM, Bloemendal HJ, Steeghs N, van de Werken HJ, Lolkema MP, Voest EE, Jager A, Cuppen E, Sleijfer S, Martens JW. The genomic landscape of 501 metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-07.

Association of genomic alterations (GAs) in circulating tumor DNA (ctDNA) with progression on abiraterone acetate (AA) or enzalutamide (enza) in advanced prostate cancer.

5048Background: Two androgen axis inhibitors, enza and AA plus prednisone, are approved for the treatment of advanced prostate cancer (aPC). Although initial responses are common with these agents,...

VALORATE: fast and accurate log-rank test in balanced and unbalanced comparisons of survival curves and cancer genomics.

The association of genomic alterations to outcomes in cancer is affected by a problem of unbalanced groups generated by the low frequency of alterations. For this, an R package (VALORATE) that estimates the null distribution and the P -value of the log-rank based on a recent reformulation is presented. For a given number of alterations that define the size of survival groups, the log-rank density is estimated by a weighted sum of conditional distributions depending on a co-occurrence term of mutations and events. The estimations are accurately accelerated by sampling across co-occurrences allowing the analysis of large genomic datasets in few minutes. In conclusion, the proposed VALORATE R package is a valuable tool for survival analysis. The R package is available in CRAN at https://cran.r-project.org and in http://bioinformatica.mty.itesm.mx/valorateR . vtrevino@itesm.mx. Supplementary data are available at Bioinformatics online.

Amplification of the bromodomain-containing protein 4 gene in ovarian high-grade serous carcinoma is associated with worse prognosis and survival.

High-grade serous carcinoma (HGSC) of the ovary is an aggressive and devastating neoplasm and the identification of novel therapeutic targets may result in a significant decrease in patient morbidity and mortality. Over the last few years, chromatin regulators have become attractive targets for cancer therapy. More specifically, bromodomain-containing protein 4 (BRD4), a protein that is associated with acetylated chromatin and transcriptional activation, has been shown to selectively regulate the transcription of key oncogenic drivers, such as CMYC, in several tumor types. The Cancer Genome Atlas (TCGA) Project has molecularly characterized the genome of ovarian serous carcinomas, which enabled us to study the association of genomic alterations of BRD4 with patient survival and clinicopathological characteristics. Our analysis using clinical and genomic data from the TCGA ovarian carcinoma samples revealed that somatic amplification of BRD4 (observed in 12% of the cases) was correlated with increased BRD4 mRNA levels and is significantly associated with worse overall and progression-free survival compared to wild-type cases. These findings support the hypothesis that future studies and trials investigating newly developed BRD4 inhibitors are required in a subset of patients with ovarian HGSC.

Association of genomic alterations with cisplatin resistance (cisR) in advanced germ cell tumors (aGCT).

4510 Background: 20% of patients (pts) with aGCT progress after initial chemotherapy (chemo), displaying at least partial cisR. We sought to characterize the genetic alterations in aGCT and identif...

Abstract 320: Association of higher Gleason grade with presence of PTEN deletion in prostatic adenocarcinoma

Abstract Prostatic adenocarcinoma (CaP) is one of the most histologically heterogeneous of epithelial malignancies. The Gleason score is widely accepted as the standard for histologic grading and determining prognosis of prostate malignancies. The tumor often presents with a multifocal distribution though the gland and different Gleason grades may be present in different foci. The current study was undertaken to compare the association of genomic alterations with the Gleason grades of individual adenocarcinoma foci. Genomic deletion of the PTEN gene in routine formalin-fixed paraffin-embedded (FFPE) pathology sections can be readily assayed by fluorescence in situ hybridization (FISH). Data from our group and others has shown that the genomic deletion of the PTEN tumor suppressor gene and the disruption of the ETS gene family, play a central role in prostate cancer and are likely to be associated with Gleason grade. In this study CaP samples were thoroughly analyzed to identify PTEN heterogeneity, within or between foci in multifocal tumors. This study was designed to retrospectively assess the overall frequency with which PTEN deletions and TMPRSS2-ERG fusion rearrangements occur individually and simultaneously, and their clinical impact through FISH analysis using well-annotated high-throughput tissue microarrays (TMAs) derived from 128 patients with CaP. In addition, four-color FISH analysis of the PTEN deletion was used to precisely detect the interstitial deletion of genomic content from this region of chromosome 10q and evaluate the tumor heterogeneity. Genomic PTEN deletion was observed in 55 of 128 (43%) patients with CaP (hemizygous = 41 and homozygous = 14 CaP). TMPRSS2-ERG fusion was observed in 58 of 129 (45%). We specifically examined the relationship between PTEN deletion and TMPRSS2-ERG fusion status, Gleason pattern and clinical behavior of CaP. Importantly, PTEN deletions were significantly associated with a higher primary Gleason pattern grade 4 (p=0.000), lymphovascular invasion (p=0.051), and higher percentage of prostate involved by tumor (p=0.0064). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (p=0.007), TMPRSS2-ERG fusions did not show any clinical correlation. In conclusion, our findings indicated that PTEN deletion FISH can be applied to CaP samples to accurately stratify patients into risk categories and to guide decision-making with respect to the optimal management of CaP patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2011-320

Association of XRCC1 gene polymorphisms with the susceptibility and chromosomal aberration of testicular germ cell tumors

It is known that many genomic and genetic alterations caused by aging or environmental factors are responsible for cancer development and progression. XRCC1 is involved in the repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. The objective of this study was to investigate the association of genomic alterations and the susceptibility of testicular germ cell tumors with XRCC1 polymorphisms. Two polymorphisms of XRCC1, Arg194Trp and Arg399Gln, were genotyped in 83 patients with testicular germ cell tumors (TGCT) and 87 male controls. Allelic imbalances (AI) were evaluated using 4 microsatellite markers in a subgroup of 50 patients. Patients with at least one Gln allele of the Arg399Gln polymorphism had an increased risk of TGCT than those with the Arg/Arg genotype (aOR=1.775, 95% CI=1.045-3.016, P=0.034). Furthermore, the increased risk associated with the Gln allele against the Arg homozygote was more strongly observed in patients with pure seminoma (aOR=2.242, 95% CI=1.149-4.374, P=0.018) or with metastasis (aOR=2.481, 95% CI=1.267-4.862, P=0.008). In the Arg194Trp polymorphism, there was no significant difference in the genotype distribution between TGCT patients and the controls. In AI analysis, the frequency of AI was significantly higher in tumors with at least one Gln allele than those with the Arg/Arg genotype in D13S317 (P=0.010) and in a combination of 4 markers (0.51+/-0.32 vs 0.32+/-28, P=0.028). Our results suggest that the Gln allele of the XRCC1 Arg399Gln polymorphism may genetically modify the development and progression of TGCT through genomic instability.

499 Association of genomic alterations at hepatitis B virus polymerase domain with viral resistance in patients with genotype C chronic hepatitis B

499 Association of genomic alterations at hepatitis B virus polymerase domain with viral resistance in patients with genotype C chronic hepatitis B