Significant Difference In Mutation Frequency Research Articles

Clinical and molecular predictors of very late recurrence in oestrogen receptor-positive breast cancer patients

BackgroundRisk of recurrence from primary ER+ breast cancer continues for at least 20 years. We aimed to identify clinical and molecular features associated with risk of recurrence after 10 years.MethodsER+ breast cancers from patients with and without recurrence were analysed with the BC360 NanoString Panel and an 87 gene targeted-exome panel. Frequency of clinical, pathologic and molecular characteristics was compared between cases (recurred between 10 and 20 years) and controls (no recurrence by 20 years) in the Very Late Recurrence (VLR) cohort. Analogous data from METABRIC were examined to confirm or refute findings.ResultsVLR cases had larger tumours and higher node positivity. Both VLR and METABRIC cases had higher clinical treatment score at 5 years (CTS5). There was a trend for fewer GATA3 mutations in cases in both VLR and METABRIC but no statistically significant differences in mutation frequency. Cell cycle and proliferation genes were strongly expressed in VLR cases. Immune-related genes and cell cycle inhibitors were highly expressed in controls. Neither of these changes were significant after correction for multiple testing.ConclusionsClinicopathologic features are prognostic beyond 10 years. Conversely, molecular features, such as copy number alterations, TP53 mutations and intrinsic subtype which have early prognostic significance, have little prognostic value after 10 years.

Research on the toxicological prognostic significance of age-related genes in endometrial cancer unveiling key factors in patient prognosis.

This study investigates the influence of aging-related genes on endometrial cancer, a prominent gynecological malignancy with rising incidence and mortality. By analyzing gene expression differences between cancerous and normal endometrial tissues, 42 aging-related genes were identified as differentially expressed. Utilizing the TCGA-UCEC sample, consensus clustering divided the samples into two molecular subgroups, Aging low and Aging high, based on their expression profiles. These subgroups showed distinct prognoses and survival rates, with the Aging high group associated with DNA repair and cell cycle pathways, and the Aging low group showing suppressed metabolic pathways and increased immune cell infiltration, suggesting a potential for better immunotherapy outcomes. Mutation analysis did not find significant differences in mutation frequencies between the groups, but a high Tumor Mutation Burden (TMB) correlated with better prognosis. A risk score model was also developed, showcasing significant prognostic power. Further analysis of the SIX1 gene revealed its overexpression in cancer cells. Drug sensitivity tests indicated that the low-risk group might respond better to chemotherapy. This research underscores the significance of aging-related genes in endometrial cancer, offering insights into their prognostic value and therapeutic potential, which could lead to personalized treatment approaches and enhanced patient management.

Abstract C078: Comprehensive evaluation for contribution of molecular, socioeconomic and disease covariates to colorectal cancer racial survival disparity of 47,178 patients

Abstract Background: Racial disparities in survival of Colorectal cancer (CRC), as well as differing frequency of driver gene mutation, have been observed before. Here we observe that self-reported race is associated with overall survival (OS) in a single institutional cohort of 47,178 patients with CRC. we conducted a systematic investigation of molecular, Socioeconomic (SES) and Disease covariates to quantitate the degree to which each influences OS. Methods: Under an approved IRB protocol, the Palantir-Foundry software system was used to query the MD Anderson (MDA) patient database to identify CRC patients and extract outcomes data and covariates. Genetic mutations that showed significant difference were included with other SES and Disease covariates in Cox-proportional hazard regression model for OS. Preliminary mediation analysis was done to quantify the contribution of each covariate to the OS disparity. Results: 47,178 patients with CRC adenocarcinoma diagnosed between 1973 and 2023 were identified and race (self-reported) was extracted (Asian 1433, 3.0%; African American (AA) 4126, 8.7%; Hispanic 4166, 8.8%; non-Hispanic White (NHW) 37453, 79.4%). Relative to NHW, AA had worse OS (HR=1.22, P= 8.03E-8), while Asians and Hispanics had better OS (HR=0.68, P= 1.06E-8 and HR=0.88, P= 7E-4). Restricting to stage 4 patients, these disparities persisted; AA HR 1.2 (p=1.7E-4) Asian HR 0.67 (p= 1.64E-5), Hispanic HR 0.88 (p= 1.4E-2) relative to NHW. Among 7,628 patients with clinical mutational testing, five genes had significant differences in mutation frequency; APC (45% Asian, 62% AA, 44% NHW, 57% Hispanics, P= 5.83E-3), KRAS (43%, 57%, 44%, 50%, P=3.43E-9), PIK3CA (13%, 23%, 17%, 17%, P=3.37E-3), BRAF (8%, 3%, 8%, 4%, P=1.15E-8), KIT (3%, 2%, 5%, 2%, p=0.046). In multivariate analysis the survival difference between Asians, Hispanics or AA compared to NHW was no longer significant (HR= 0.91, P=0.59, HR= 0.87, P=0.21 and HR=1.14, P= 0.18). In contrast KRAS (HR= 1.5, P=9.22E-9), BRAF (HR= 1.64, P=1E-4) APC mutation (HR= 0.77, P=1E-4) were independently associated with OS, as was higher ECOG (HR= 1.39, P=7.14E-23), higher stage (HR= 1.5, P=3.57E-20), higher national area deprivation index (ADI) quantile (HR=1.08, P= 2.7E-3), being married (HR=1.2, P= 1.52E-2), right side colon tumor (HR=1.22, P= 1.03E-2), poorly differentiated tumors (HR= 1.2, P=1.47E-2), undergoing surgical intervention (HR= 0.47, P=1.54E-29) and MSI-high (HR= 0.41, P=2.16E-6). In our single institution study preliminary mediation analysis showed that ADI, marital status, right sided affection, KRAS mutation, BRAF mutation were the main drivers of the survival disparities in contrast to stage, grade, performance status, surgical intervention and MSI-status. Conclusions: Racial survival disparity is complex and multifactorial. Our single center systematic evaluation showed that SES, driver gene mutations and site of colon affected by the tumor made an important contribution to the racial survival disparity. Further investigation of germline variation, and treatment response is warranted. Citation Format: Mahmoud Yousef, Abdelrahman Yousef, Mohammad Zeineddine, Saikat Chowdhury, Mohammad Fanaeian, Naoko Little-Jackson, Mark Knafl, Kristin Alfaro-Munoz, Abinheet Uppal, Scott Kopetz, Wenyi Wang, Jason Willis, John Paul Shen. Comprehensive evaluation for contribution of molecular, socioeconomic and disease covariates to colorectal cancer racial survival disparity of 47,178 patients [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C078.

Analysis of ATM germline mutations in solid tumors from Chinese patients.

10586 Background: Ataxia-telangiectasia mutated (ATM) is a tumor suppressor genes and plays an important role in the repair of DNA double-strand breaks (DSBs). Germ-line mutations of ATM gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Novel therapies are in development that may improve the response to therapy of patients with ATM-deficient cancers including targeted therapy and immunotherapy. Nevertheless, the knowledge of incidence of ATM germline mutations in solid tumor remains poorly understood. Methods: We identified 19248 malignant solid tumors patients without selecting age or family history in a retrospective cohort. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines.The patients were divided into two groups, P/ LP group (with pathogenic or likely-pathogenic mutations), and Non-P/LP group (neither pathogenic nor likely-pathogenic mutation). Results: In 19248 patients with pan-cancer, 76 patients were found 76 heterozygous pathogenic or likely pathogenic germline mutations in ATM gene and the mutation frequency was 0.39%.Among these 76 carriers, 71 (93.4%) carried frameshift, nonsense or splice mutations (33 for frameshift,21 for missense and 17 for splice mutations). 4 carried missense mutations and 1 carried intron mutations. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained cancers were pancreatic cancer (1.0%,7/692), breast cancer (0.71%,3/423), gastric cancer (0.6%,7/1094), The median age of group P/LP and non-P/LP group was 64 and 63 in pancreatic cancer，62 and 53 in breast cancer and 62 and 61 in gastric cancer. The three genes with the most somatic mutations were TP53, MUC16 and KRAS in P/LP group and were TP53, MUC16 and EGFR in non-P/LP group. There was no significant difference in mutation frequency of the four genes. The media TMB in P/LP group and non-P/LP group were 3.55 and 2.84 respectively and there was no statistical difference. In P/LP group，only one patients is high microsatellite instability who carryied a MLH1 and a ATM pathogenic mutation. Conclusions: This was the first report of the incidence of ATM germline mutations in Chinese solid tumors which expanded the understanding of ATM and provided a direction for clinical trial design of novel therapies. The relationship between germline mutations and cancer susceptibility will be studied in the future.

Molecular Landscape and Prognostic Biomarker Analysis of Advanced Pancreatic Cancer and Predictors of Treatment Efficacy of AG Chemotherapy.

PurposeAlthough mutational analysis of pancreatic cancer has provided valuable clinical information, it has not significantly changed treatment prospects. The purpose of this study is to further investigate molecular alterations in locally advanced pancreatic cancer and identify predictors of the efficacy of nab-paclitaxel plus gemcitabine (AG) chemotherapy.Experimental designTumor samples from 118 pancreatic cancer patients who received AG chemotherapy as first-line treatment were sequenced and genomic profile was generated. Molecular alterations and the involved signaling pathways were analyzed. Genes with a significant difference in mutation frequency between primary and metastatic tumors were identified, and prognostic-related mutant genes were screened using SPSS version 22.0.ResultsThe most common altered genes in the patients were KRAS (94.9%), TP53 (81.4%), CDKN2A (36.4%), and SMAD4 (22.9%). The mutational frequencies of CDKN2B (14.8% vs. 0%, p = 0.001), FAT3 (7.4% vs. 0%, p = 0.041), MTAP (13% vs. 1.6%, p = 0.023), and SMAD4 (31.4% vs. 15.6%, p = 0.049) in metastatic tumors were significantly higher than that in primary tumors. TP35 and KRAS mutations were significantly correlated with objective response rate, while EPHA7, RNF43, and HMGA2 mutations were significantly correlated with disease control rate. Additionally, patients with TGFR2B, FGF23, EPHA7, SMARCA4, CARD11, ADGRA2, CCNE1, and ACVR2A alterations had a worse overall survival. Further, EPHA7, CARD11, NOTCH1, GATA6, ACVR2A, and HMGA2 mutations indicated undesirable progression-free survival.Conclusions CDKN2B, FAT3, MTAP, and SMAD4 may be biomarkers that distinguish primary tumors from metastases. EPHA7 mutation may serve as a prognostic biomarker to predict the treatment efficacy of AG chemotherapy in locally advanced pancreatic cancer.

Comparative Genomic Analysis Reveals Genetic Variations in Multiple Primary Esophageal Squamous Cell Carcinoma of Chinese Population.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and lethal malignant tumors. The incidence of malignant transformation of esophageal mucosa increases greatly due to long-term exposure to factors such as smoking, drinking, and poor eating habits. Furthermore, multiple primary tumors could occur synchronously or asynchronously in the upper aerodigestive tract, especially in the esophagus, adding difficulty to the treatment of ESCC. Genetic mutations are important during the malignant transformation from normal mucosa to esophageal cancer, but the underlying mechanism has not been fully elucidated. In this study, we used whole-exome sequencing (WES) to profile genetic variations in physiologically normal mucosa (PNM) and ESCC tumors, as well as PNM of non-ESCC subjects. We found significant differences in mutation frequencies of NOTCH1 and NOTCH2, copy number variations (CNVs) at both gene and chromosomal arm levels, and cancer-related HIPPO, WNT, and NRF2 signaling pathways between ESCC tumors and normal mucosa. Our analysis of both primary tumors and paired PNM in bifocal ESCC revealed three different primary tumor evolution modes, and the most common mode exhibited a complete genomic divergence in all the samples from the same patient. Furthermore, the mutation frequency of TP53 was significantly higher in ESCC cases than that in non-ESCC cases. Overall, our results provide important evidence for further elucidating the mechanisms of genetic mutations underlying the cause of ESCC.

RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm.

Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.

New factors of pterygium occurrence and recurrence after surgical treatment

Background. Occurrence and recurrence of pterygium after surgical treatment are still urgent problems of modern ophthalmology. The purpose was to determine the main factors leading to the occurrence and recurrence of pterygium after surgical treatment. Materials and methods. We observed 203 patients (232 eyes) with pterygium. There were 108 men and 95 women. The age of patients ranged from 35 to 65 years. The duration of the disease is 2.5–2.7 years. Patients underwent surgical treatment for pterygium by the McReynolds’ method forming a cul-de-sac, by the Artl method with its incision, and the McReynolds and Artl methods using 0.02% solution of mitomycin C. The patients were examined in 3, 6 months, and one year after surgery. The statistical analysis of the results of clinical trials was performed using the software package SPSS 11.0, MedStat (Lyakh Y.E., Guryanov V.G., 2004–2012), MedCalc (MedCalc Software bvba, 1993–2013). Results. The results of clinical studies have found that the frequency of pterygium recurrence after traditional surgical interventions by the McReynolds method, the McReynolds method using 0.02% solution of mitomycin C, by the traditional Arlt method, the Arlt me-thod using 0.02% solution of mitomycin C in 3 months was 20, 17, 15, and 8.7 %, respectively; in 6 months — 29.5, 27, 27, and 26 %, respectively; after 1 year — 26.5, 26.5, 30.6, and 37 %, respectively. Long-term recurrence of pterygium did not differ significantly (p < 0.05). Viral infection was found in pterygium tissue in 50.9 % of cases, including herpesviruses (33.6 %) and human papillomavirus (HPV, 34.0 %). Among herpesviruses, herpes simplex virus (HSV) was found in 15.1 % of cases, cytomegalovirus (CMV) in 7.3 %, and Epstein-Barr virus (EBV) in 11.2 % of cases. The regression analysis showed an association of HSV with stage II and stage III pterygium (p < 0.05). No such dependencies were found for CMV and EBV. There was a relationship of HPV with the I–III stages of pterygium (p < 0.01). There were types 6 (34.2 %), 11 (24.1 %), 16 (21.5 %), and 18 (20.2 %) among HPV. Types 6 and 11 were mainly detected at the first stages and were not detected in stage IV; types 16 and 18 were not detected in stage I (p = 7.9e-04). Among other types, only HPV6 was associated with the I and III stages of pterygium (p < 0.05). Double mixed infection was detec-ted in 32.1 % of patients. The most common was the combination of HSV and HPV (30.6 % of all cases of mixed infection), three viruses — in 2.5 % of cases in the combination of HSV + CMV + HPV and HSV + EBV + HPV. It was first established that the V600E mutation of the BRAF gene was detected in 35.3 % of cases of pterygium. No significant difference in mutation frequency depending on the sex and age of patients was found. The frequency of mutation by stages increased from 21.3 % at stage I to 57.7 % at stage IV (p = 0.0003). The regression analysis showed a strong progressive association with the presence of the BRAF gene V600E mutation with the pterygium stage and, therefore, its progression. Conclusions. Thus, it was proved that the presence of HSV, HPV, and mutation V600E of the BRAF gene significantly influenced the occurrence and progression of pterygium after surgical treatment.

Investigating the Relationship between Tumor Necrosis Factor Alpha-308 and Interleukin-1beta C+3953T Polymorphisms with Male Fertility in Erbil Province

Male infertility is influenced by psychological, biological and environmental factors. Nowadays, the morphological change of genes and biological molecules are the focus of attention. Therefore, this study was conducted with the aim of investigating the relationship between tumor necrosis factor alpha-308 and interleukin-1beta C+3953T polymorphisms with male fertility in Erbil province. This study was conducted between 2020 and 2021 on 270 men who referred to the infertility center in Erbil, Iraq, with infertility problems. The sampling was purposeful and the samples were divided into three groups of 90 people with the characteristics of the first group without fertility problems, the second group with primary infertility and the third group with secondary infertility. Blood samples were taken from each sample and the samples were sent to the laboratory for deoxyribonucleic acid extraction and allele analysis. A polymerase chain reaction machine was used for this purpose. Statistical package for the social sciences version 23 software and descriptive statistical tests, chi-square, odds ratio and conditional regression were used to analyze the obtained data. The results of tumor necrosis factor alpha-308 genotype showed the frequency of alleles in three groups of men, it can be concluded that there is a significant difference between the three groups of men in terms of mutation frequency and fertility (p≤0.001). The results of interleukin-1beta C+3953T genotype have shown that there is a significant difference in mutation frequency and finally fertility in three groups of men (p≤0.001). The tumor necrosis factor alpha-308 genotype GA and GG alleles have a significant relationship with male fertility. In genotype interleukin-1beta C+3953T, CT and CC alleles have a significant relationship with male fertility. The results of this study showed that tumor necrosis factor alpha-308 genotype and interleukin-1beta C+3953T genotype were identified as important risk factors in male infertility.

Comprehensive Analysis of the Effects of Genetic Ancestry and Genetic Characteristics on the Clinical Evolution of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC), a kind of malignant cancer, is associated with increasing morbidity and mortality. Patients with different genetic ancestries may respond differently to clinical treatment. The limited understanding of the influence of genetic ancestry and genetic characteristics on OSCC impedes the development of precision medicine. To provide a reference for clinical treatment, this study comprehensively analyzed multigenomic differences in OSCC patients with different genetic ancestries and their impact on prognosis. An analysis of data from OSCC patients with different genetic ancestries in The Cancer Genome Atlas (TCGA) showed that the overall survival (OS) of African (AFR) patients was lower than that of primarily European (EUR) patients, and differences were also observed in the tumor–stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs), which are associated with prognosis. FAT1 is a key mutant gene in OSCC, and it has inconsistent effects on clinical evolution for patients with diverse genetic characteristics. PIKfyve and CAPN9 showed a significant difference in mutation frequency between EUR and AFR; PIKfyve was related to Ki-67 expression, suggesting that it could promote tumor proliferation, and CAPN9 was related to the expression of Bcl-2, promoting tumor cell apoptosis. A variant methylation locus, cg20469139, was correlated with the levels of PD-L1 and Caspase-7 and modulated tumor cell apoptosis. A novel ceRNA model was constructed based on genetic ancestries, and it could accurately evaluate patient prognosis. More importantly, although T cell dysfunction scores could determine the potential of tumor immune escape, the efficacy was obviously affected by patients’ genetic ancestries. To provide patients with more precise, personalized therapy and to further improve their quality of life and 5-year survival rate, the influence of genetic ancestry should be fully considered when selecting treatments.

Role of RNF213 polymorphism in defining quasi-moyamoya disease and definitive moyamoya disease.

Quasi-moyamoya disease (QMMD) is moyamoya disease (MMD) associated with additional underlying diseases. Although the ring finger protein 213 (RNF213) c.14576G>A mutation is highly correlated with MMD in the Asian population, its relationship to QMMD is unclear. Therefore, in this study the authors sought to investigate the RNF213 c.14576G>A mutation in the genetic diagnosis and classification of QMMD. This case-control study was conducted among four core hospitals. A screening system for the RNF213 c.14576G>A mutation based on high-resolution melting curve analysis was designed. The prevalence of RNF213 c.14576G>A was investigated in 76 patients with MMD and 10 patients with QMMD. There were no significant differences in age, sex, family history, and mode of onset between the two groups. Underlying diseases presenting in patients with QMMD were hyperthyroidism (n = 6), neurofibromatosis type 1 (n = 2), Sjögren's syndrome (n = 1), and meningitis (n =1). The RNF213 c.14576G>A mutation was found in 64 patients (84.2%) with MMD and 8 patients (80%) with QMMD; no significant difference in mutation frequency was observed between cohorts. There are two forms of QMMD, one in which the vascular abnormality is associated with an underlying disease, and the other in which MMD is coincidentally complicated by an unrelated underlying disease. It has been suggested that the presence or absence of the RNF213 c.14576G>A mutation may be useful in distinguishing between these disease types.

Glycogen Metabolism Predicts the Efficacy of Immunotherapy for Urothelial Carcinoma

Urothelial cancer (UC) is one of the common refractory tumors and chemotherapy is the primary treatment for it. The advent of immune checkpoint inhibitors (ICI) has facilitated the development of treatment strategies for UC patients. To screen out UC patients sensitive to ICI, researchers have proposed that PD-L1, tumor mutation burden and TCGA molecular subtypes can be used as predictors of ICI efficacy. However, the performance of these predictors needs further validation. We need to identify novel biomarkers to screen out UC patients sensitive to ICI. In our study, we collected the data of two clinical cohorts: the ICI cohort and the TCGA cohort. The result of the multivariate Cox regression analysis showed that glycogen metabolism score (GMS) (HR = 1.26, p = 0.017) was the negative predictor of prognosis for UC patients receiving ICI treatment. Low-GMS patients had a higher proportion of patients achieving complete response or partial response to ICI. After the comparison of gene mutation status between high-GMS and low-GMS patients, we identified six genes with significant differences in mutation frequencies, which may provide new directions for potential drug targets. Moreover, we analyzed the immune infiltration status and immune-related genes expression between high-GMS and low-GMS patients. A reduced proportion of tumor-associated fibroblasts and elevated proportion of CD8+ T cells can be observed in low-GMS patients while several immunosuppressive molecules were elevated in the high-GMS patients. Using the sequencing data of the GSE164042 dataset, we also found that myeloid-derived suppressor cell and neutrophil related signature scores were lower in α-glucosidase knockout bladder carcinoma cells when compared to the control group. In addition, angiogenesis, classic carcinogenic pathways, immunosuppressive cells related pathways and immunosuppressive cytokine secretion were mainly enriched in high-GMS patients and cell samples from the control group. Finally, we suspected that the combination treatment of ICI and histone deacetylase inhibitors may achieve better clinical responses in UC patients based on the analysis of drug sensitivity data. In conclusion, our study revealed the predictive value of GMS for ICI efficacy of UC patients, providing a novel perspective for the exploration of new drug targets and potential treatment strategies.

The genomic landscape of Chinese patients with upper tract urothelial carcinoma.

e16583 Background: Upper tract urothelial carcinoma (UTUC) is known to have a distinct aggressive clinical phenotype and its genomic characterization is poorly understood, especially in Asian population. In this study, we aimed to characterize the genomic landscape of Chinese UTUC patients and explore the clinical relevance, which is the largest cohort of UTUC to date. Methods: Overall, 122 Chinese patients with UTUC were enrolled. Tumor and germline DNA from patients were analyzed using a targeted next-generation sequencing assay to identify somatic mutations in 520 cancer associated genes. Mutations like deletion, amplification and gene fusion were included. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also evaluated. The frequency of genomic alterations in patients with UTUC was compared with that of the Western counterpart from previous studies. Results: In total, 13 low-grade and 109 high-grade UTUC patients were included in this study. The most frequent genomic alterations were identified in genes like TERT (50.0%; 61.5% low-grade vs 48.6% high-grade), KMT2D (48.4%; 61.5% vs 46.8%), FGFR3 (41.0%; 69.2% vs 37.6%), TP53 (37.7%; 7.7% vs 41.3%), CDKN2A (22.1%; 23.1% vs 22.0%), KDM6A (20.5%; 15.4% vs 21.1%) with different mutation frequencies in the two subgroups of patients. Despite the overall similarity (including FGFR3, ARID1A and CDKN2A), the comparison between our cohort and the two Western UTUC cohorts (n = 119, 24 low-grade and 95 high-grade) revealed significant differences in mutation frequencies of KMT2D (48.4% vs 36.1%), TERT (50.0% vs 26.9%), TP53 (37.7% vs 21.9%) and KDM6A (20.5% vs 32.8%) . Chi-square analysis revealed that patients with history of other cancers (4/17 vs. 3/105, P = 0.001) were more likely to have a MSI-high status. In addition, females (9/44 vs. 6/78, P = 0.039) and patients with cancer history (6/17 vs. 9/105, P = 0.002) were more likely to have high TMB (≥20 mutations/Mb; median: 6.48 mutations/Mb). At last, the frequency of germline P/LP variants were also similar but different in the spectrum between our cohort and the Western UTUC population. Differences in mutation frequency of APC (0 vs 2.6%), BRAC2 (2.6% vs 0.9%), CHEK2 (0.3% vs 1.8%), MSH2 (2.6% vs 5.3%) and MSH6 (0 vs 1.8%) were significant. Conclusions: This study revealed that Chinese UTUC patients had a similar frequency of genomic alterations with western patients. However, there were significant differences in the prevalence of several mutated genes including KMT2D, TERT, TP53 and KDM6A, suggesting the ethnicity differences between the two populations. Our findings laid the foundation of a deeper understanding of UTUC biology and will provide potential targets for the development of precision therapies in UTUC.

Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing

BackgroundThymic carcinoma is a rare mediastinal neoplasm, and little is known about its genetic variability, which has hampered the development of targeted therapies. Patients and MethodsWe tested a next-generation sequencing panel containing 50 common cancer-related genes in 48 cases of thymic carcinoma and 6 cases of thymic neuroendocrine tumor. ResultsWe detected 42 variant calls in 21 of 54 cases. There was no significant difference in mutation frequency between thymic carcinoma and thymic neuroendocrine tumors. Among these, TP53 was the most frequently mutated gene (18.5%), followed by KIT (7.4%) and PDGFRA (5.6%). According to the gene pathways and groups, the p53 pathway, including TP53 and ATM, was most frequently affected (20.4%), followed by the receptor tyrosine kinase (RTK)/RAS pathway (18.5%) and PI3K pathway (5.6%). According to the OncoKB, an expert-guided precision oncology knowledge base, 7 genes among 10 cases (18.5%) were annotated with level 1 evidence, suggesting potentially therapeutic targets. Prognostic analyses, conducted in thymic squamous cell carcinomas, revealed that tumor cases harboring gene mutations in RTKs, including KIT (7.4%), PDGFRA (5.6%) and EGFR (3.7%), were significantly associated with a worse overall survival time (P = .0481). Among clinicopathologic factors, the advanced Masaoka stage was marginally associated with a worse overall survival (P = .0757). In the subsequent multivariate analysis, neither of the factors achieved statistical significance. ConclusionsIn this preliminary next-generation sequencing study, we unexpectedly found evidence suggesting that several gene mutations might be therapeutic targets. The gene mutations in RTKs may be a valuable prognostic factor in thymic squamous cell carcinoma.

Tumor genetic heterogeneity analysis of chronic sun-damaged melanoma.

Chronic sun‐damaged (CSD) melanoma represents 10%–20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra‐tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra‐deep targeted sequencing of 40 cancer‐associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in‐transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma‐related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.

ASXL1 Mutations Detectable at Diagnosis May Predict Response to Imatinib in Patients with Chronic Myeloid Leukemia

Clinical resistance to tyrosine kinase inhibitors (TKI) remains a significant problem in the therapy of patients with chronic myeloid leukemia (CML). Although BCR-ABL1-kinase domain mutations are the major cause of resistance to TKI, some patients manifest primary or develop secondary resistance to TKI without detectable BCR-ABL1 mutations. We aimed to assess the prevalence of additional gene mutations in a group of 50 patients with primary (n = 26) or secondary resistance (n = 24) to TKI, in most cases to imatinib (n = 49) and in one to dasatinib. We employed ~1000 genes custom target enrichment kit and next-generation sequencing on Illumina platform, as well as Sanger sequencing. In 21 patients, we were able to match and analyze paired samples collected at diagnosis (before treatment) and at the time of resistance and in five other cases we analyzed additional samples collected later during TKI-resistant chronic phase or in blast crisis. The most frequent genetic aberrations detected at the time of TKI-resistance were mutations in ASXL1 and BCR-ABL1 kinase domain coding sequence, present in 28% (14/50) and 26% (13/50) of patients, respectively. Both genes were mutated in 12% of patients (6/50), while 30% (15/50) had either ASXL1 or BCR-ABL1 mutations alone. Non-recurrent genetic aberrations in other genes were also noted in single patients (e.g. DNMT3A mutations). According to COSMIC database, all but three ASXL1 mutations detected in this study were previously described in hematologic malignancies and all (including the novel ones) are predicted to introduce stop codons or cause frameshifts in codon range of 512-943, thus truncating the protein before the C-terminal PHD domain. Among patients with available paired samples three had more than one ASXL1 mutation at various time points and in all of them we observed dynamics of specific ASXL1 mutations, related partially to the leukemic cell content in the sample but also providing evidence of clonal evolution (Table 1). In most of patients with concurrent ASXL1 and BCR-ABL1 mutations, we observed that both mutations were present with similar variant allele frequency (VAF), suggesting that ASXL1 mutations occur in Philadelphia-positive leukemic clones (Table 2). ASXL1 mutation frequency was significantly higher in TKI-resistant patients, than in our previously characterized group of CML patients without resistance, who achieved major molecular response (28% ; 14/50 vs 5.6% ; 2/36, respectively, p = 0.0105, Fisher exact test). All ASXL1-mutated patients with secondary (n = 1) or primary resistance (n = 5) for whom diagnostic sample was available, carried ASXL1 mutation also at the time of diagnosis. No significant difference in mutation frequency was found between patients with primary and secondary resistance (ASXL1 mutation, 26.9% vs 29.2% ; BCR-ABL1 mutation, 15.4% vs 37.5%). Our results provide evidence that preexisting ASXL1 mutations in BCR-ABL1-positive leukemic clone present at diagnosis may have impact on clinical response to imatinib and may be useful in assessing the risk of treatment failure. Disclosures Niesiobedzka-Krezel: Novartis: Honoraria. Seferynska:Novartis: Honoraria. Gora Tybor:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sacha:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Differentially mutated subnetworks discovery

ProblemWe study the problem of identifying differentially mutated subnetworks of a large gene–gene interaction network, that is, subnetworks that display a significant difference in mutation frequency in two sets of cancer samples. We formally define the associated computational problem and show that the problem is NP-hard.AlgorithmWe propose a novel and efficient algorithm, called DAMOKLE, to identify differentially mutated subnetworks given genome-wide mutation data for two sets of cancer samples. We prove that DAMOKLE identifies subnetworks with statistically significant difference in mutation frequency when the data comes from a reasonable generative model, provided enough samples are available.Experimental resultsWe test DAMOKLE on simulated and real data, showing that DAMOKLE does indeed find subnetworks with significant differences in mutation frequency and that it provides novel insights into the molecular mechanisms of the disease not revealed by standard methods.

MP06-03 RACE BASED DISPARITIES IN GENE EXPRESSION AND MUTATIONS IN BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Epidemiology & Evaluation I1 Apr 2018MP06-03 RACE BASED DISPARITIES IN GENE EXPRESSION AND MUTATIONS IN BLADDER CANCER Kalen Rimar, Joshua Meeks, Sarah Psutka, and Edward Schaeffer Kalen RimarKalen Rimar More articles by this author , Joshua MeeksJoshua Meeks More articles by this author , Sarah PsutkaSarah Psutka More articles by this author , and Edward SchaefferEdward Schaeffer More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.195AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES African Americans (AA) with urothelial carcinoma (UC) of the bladder have been shown to have worse cancer-specific (CSS) and overall survival (OS). Though several factors including socioeconomic status, access to care, and advanced stage at presentation have been proposed, the cause of this disparity remains undefined. Our objective was to compare bladder cancer gene expression and mutations between AA and Caucasian patients to assess whether the observed disparities in oncologic outcomes could be explained by associated mutational differences. METHODS Using the Bladder/Urothelial Carcinoma Cancer Genome Atlas (BC-TCGA, Provisional) we compared mutation type, frequency, signature, and gene expression between AA and Caucasian patients. We also compared differentially expressed genes according to race across all TCGA provisional cancer datasets that contained a minimum of 10 AA and 10 Caucasian patients per arm (19 of 33). RESULTS We identified 23 AA and 323 non-AA patients in the UC-TCGA dataset with available whole genome and RNA sequencing. There was no significant difference in the total mutation load between Caucasian and AA (range = 1 to 4472 variants/genome, n = 316, median = 240.5 vs. range = 82 to 562 variants/genome; n = 22, median=225.5, p=0.228). The majority of DNA substitution mutations in both Caucasian and AA patients were C->T, and there was no significant difference in frequency (p=0.33). There were no significant differences in Catalogue of Somatic Mutations in Cancer (COSMIC) signatures between the two groups (p=0.3). There was no significant difference in mutation frequency of known UC driver genes (TP53, MLL4, KDM6A, MLL3, PIK3CA, RB1, EP300, ERBB2) by race. Yet, we were able to identify 14 genes with significant differential expression according to race of which HIST1H2BD, L1TD1, and LRRC37A2 were associated with inferior OS (p<0.005, p=0.03, p=0.02). Notably, analyses of TCGA datasets revealed a conserved panel of genes differentially expressed by race across multiple cancers types involved in cell division and nucleosome function. CONCLUSIONS AA and Caucasians with UC have similar mutation type, frequency, and signature. However several differentially expressed genes within the UC were observed between AA and Caucasians and these differences remain consistent across many cancer types within the TCGA suggesting epigenetic regulation. Some of these gene expression differences may be independent of cancer. Nevertheless, the extent to which this differential gene expression may predispose to variable disease outcomes across race warrants further study. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e52-e53 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Kalen Rimar More articles by this author Joshua Meeks More articles by this author Sarah Psutka More articles by this author Edward Schaeffer More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3.

BACKGROUNDIn contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2‐targeted therapies.METHODSIn this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer‐related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas.RESULTSA total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB‐mutated samples, and ERBB3‐mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2‐amplified samples compared with wild‐type CRC samples (51.8%), and ERBB2‐ or ERBB3‐mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways.CONCLUSIONSAlthough observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti‐HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2‐positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti‐HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358‐73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases.

Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups. Of interest, BCL7A, BRWD3, and AUTS2 demonstrate significantly higher mutation frequencies among AA cases. These genes are all involved in translocations in B-cell malignancies. Moreover, we detected a significant difference in mutation frequency of TP53 and IRF4 with frequencies higher among CA cases. Our study provides rationale for interrogating diverse tumor cohorts to best understand tumor genomics across populations.