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A, chromosome 13; B, chromosome 14. Red: probe in the deleted region; Green, pericentromeric probe. Each nucleus contains two green spots and one red spot, indicating that the tumor is diploid for chromosomes 13 and 14 but has heterozygous deletions in the regions tested by the red probes.
Source publication
Germline BRCA1 or BRCA2 mutations account for 20-30% of familial clustering of breast cancer. The main indication for BRCA2 screening is currently the family history but the yield of mutations identified in patients selected this way is low.
To develop more efficient approaches to screening we have compared the gene expression and genomic profiles...
Citations
... Consideration of the genomic structure of BRCA2-driven tumors provides further insight into the specific enrichment of RB1 loss in this context. These genes are both co-located on chromosome 13q, and previous work suggested that biallelic inactivation of BRCA2 in gBRCA2-driven tumors often occurs through LOH as a result of loss of a large chromosomal segment including the WT allele 44,45 . To confirm this finding, we analyzed the data from our cohort, which demonstrated a clear co-occurrence of BRCA2 and RB1 LOH ) in gBRCA2 tumors (n = 61, 77.2% of evaluable cases; OR 8.70, 95% CI 5.01 -15.81, p < 0.0001) (Fig. 4a). ...
... The majority (75%, n=6) of post-CDK4/6i somatic RB1 variants found in the gBRCA2 tumors were short indels. Microhomology-mediated end joining (MMEJ) is a commonly implicated back-up DNA repair mechanism demonstrated in HRD-driven tumors 44,45 , and can be identified by a characteristic pattern of microhomology flanking a short deletion. Indeed, 66% of short indels resulting in RB1-loss post-CDK4/6i were reflective of MMEJ. ...
Germline and somatic variants that drive breast tumorigenesis and therapeutic sensitivity are widely prevalent. The clinical and biologic significance of co-occurring disease-defining germline and somatic events have yet to be defined and exploited. Using multiple, independent clinical cohorts comprising over 4500 patients, we identify that pathogenic RB1 variants are enriched in gBRCA2-associated cancers, and manifest poor outcomes on standard-of-care frontline CDK4/6i plus antiestrogen combinations. We demonstrate gBRCA2-associated cancers commonly give rise to allelic configurations manifesting RB1 heterozygosity and readily lose the second copy through gBRCA2 loss-mediated homologous recombination deficiency (HRD)under the therapeutic pressure of CDK4/6i. The findings unveil a novel therapeutic strategy of targeting the underlying HRD through PARPi prior to CDK4/6i to intercept the deleterious RB1-loss trajectory. The work reveals how germline-somatic driven genomic configurations can shape treatment responses and be exploited in biomarker-directed clinical strategies.
... Interestingly, a number of amplicons/deleted regions identified in this cohort are known to be associated with breast cancer/aggressive basal breast cancer, such as gains of 1q, 8p11-12, 8q, 12p13, 13q34, 17q, and 19q and deletions of 3p, 4p16.3, 8p, 11p15, 17p, and 19p13 (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58). Documented breast cancer oncogenes (NOTCH2, ENSA, PIK3CA, CD44, WT1, BCL2L2, AKT2, and TFF3) and tumor suppressors (BRCA2 and PRKCDBP) reside or are in close proximity to some of these significantly amplified/deleted genomic regions, and these alterations potentially contribute to TNBC progression and BrM development. ...
... WT1, which also resides at 11p13, has been shown to promote a mesenchymal phenotype in breast cancer cells as well as to elicit resistance to taxane therapy (47). Regions of 1q were also commonly amplified, which supports a known role for this genomic location in breast cancer development (48). The amplification and increased expression of ENSA (1q21.3) ...
... In primary TNBC, notable amplicons were associated with both arms of chromosomes 1 and 8. These locations are associated with breast cancer cytogenetics and pathology (48,78,79) and harbor genes (NOTCH2 and RCP, respectively) associated with breast cancer etiology (49,80). There were also several notable alterations specific to BrM. ...
Background
Triple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.
Methods
Whole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.
Results
Primary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.
Conclusions
BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.
... Its effect may be particularly exacerbated in Nigerian patients as HR−/HER2+ has been reported to be enriched within younger Nigerian patients for reasons that are poorly understood 8 . 14q LOH has been reported in BRCA2 mutation carriers using array-CGH 32,33 . We also observed 14q LOH in all BRCA2 carriers; however, the presence of 14q LOH in BRCA2-negative tumors suggests that this CNA event is present more widely in breast cancer than previously described. ...
Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers ( ZNF217 and SYPL1 ) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
... Its effect may be particularly exacerbated in Nigerian patients as HR-/HER2+ has been reported to be enriched within younger Nigerian patients for reasons that are poorly understood 8 . 14q LOH has been reported in BRCA2 mutation carriers using array-CGH 30,31 . We also observed 14q LOH in all BRCA2 carriers, however the presence of 14q LOH in BRCA2-negative tumors suggests that this CNA event is present more widely in breast cancer but has been understudied. ...
Black women of African ancestry experience more aggressive breast cancer with higher mortality rates than White women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast tumors, with RNA-seq in a subset, from indigenous African patients in Nigeria in comparison to The Cancer Genome Atlas (n=76) revealed a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations and a 10.5-year younger age at diagnosis. We also found evidence for non-coding mutations in two novel drivers ( ZNF217 and SYPL1 ) and a novel INDEL signature strongly associated with African ancestry proportion. This comprehensive analysis of an understudied population underscores the need to incorporate diversity of genomes as a key parameter in fundamental research with potential to tailor clinical intervention and promote equity in precision oncology care.
... Its effect may be particularly exacerbated in Nigerian patients as HR−/HER2+ has been reported to be enriched within younger Nigerian patients for reasons that are poorly understood 8 . 14q LOH has been reported in BRCA2 mutation carriers using array-CGH 32,33 . We also observed 14q LOH in all BRCA2 carriers; however, the presence of 14q LOH in BRCA2-negative tumors suggests that this CNA event is present more widely in breast cancer than previously described. ...
Breast cancer is a heterogeneous disease and the incidence to mortality ratio is highest for women of African ancestry. Paucity of data from non-European ancestry groups limits our understanding of the underlying etiological differences or alternative routes to progression that may explain differential outcomes. To examine the contribution of genomic differences, we performed high-depth whole-genome sequencing on 100 breast tumors (90X) and their paired normal samples (30X) from indigenous African women with breast cancer in Southwest Nigeria and performed comparative analysis with 84 TCGA whole genome sequences of breast tumor/normal pairs (46 White, 30 African American and 8 samples representing other ethnicities). High confidence somatic single nucleotide variants (SNVs) were obtained by using MuTect and Strelka. To analyse intra-tumoral heterogeneity (ITH), Battenberg and DPClust were used to call copy number aberrations (CNA) and cluster somatic SNVs based on cancer cell fraction (CCF) respectively. We find that in the HR-/HER2+ subtype, clonal losses of chromosome 14q are highly enriched in Nigerians (41%) but absent in the Whites even though the proportion of this subtype was comparable between the two groups (42% and 33% respectively). This is an interesting observation since not only 14q loss is known to be an event associated with breast cancer aggressiveness, but HR-/HER2+ has also been reported to be enriched within the relatively younger Nigerian patients with breast cancer. This may in part explain inter-ethnic disparity in survival. Also, somatic SNV clustering analysis showed that Nigerian cancers have a higher level of ITH than Whites, which may explain the pronounced aggressiveness of breast cancer in women of African ancestry. In contrast, early drivers (e.g. TP53 and ) and whole genome duplication rates were mostly similar between the groups. Our observations suggest differences in the underlying evolutionary trajectories of breast cancer across ethnic backgrounds. These data underscore the need for larger and more in-depth studies of diverse cancer genomes and, if validated, may translate into clinical intervention opportunities tailored to women of African ancestry and accelerate progress in precision cancer care.
Note: This abstract was not presented at the meeting.
Citation Format: Naser Ansari-Pour, Jason J. Pitt, Stefan Dentro, Dominic Fitzgerald, Yonglan Zheng, Toshio F. Yoshimatsu, Padma Rajagopal, Andreas Gruber, Ayodele Sanni, Olayiwola Oluwasola, Mustapha Ajani, Abayomi Odetunde, Abiodun Popoola, Adeyinka Falusi, Temidayo Ogundiran, John Obafunwa, Oladosu Ojengbede, Nasiru Ibrahim, Kevin P. White, Dezheng Huo, Peter Van Loo, David C. Wedge, Olufunmilayo Olopade. The life history of breast cancer in Nigerian women: Evidence for ethnic differences in tumor evolution based on whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-300.
... Module 36 was enriched in chr14q, the cytoband where the high-level alterations at 14q31.3-32.12 were found in breast cancer from Shadeo and Lam (2006). Besides, the deletion of chr14q is a common feature of tumors with BRCA2 mutations (Rouault et al., 2012). Modules 5 was specifically associated with TME related biological process such as extracellular matrix (ECM), cell adhesion and cell migration. ...
Improved cancer prognosis is a central goal for precision health medicine. Though many models can predict differential survival from data, there is a strong need for sophisticated algorithms that can aggregate and filter relevant predictors from increasingly complex data inputs. In turn, these models should provide deeper insight into which types of data are most relevant to improve prognosis. Deep Learning-based neural networks offer a potential solution for both problems because they are highly flexible and account for data complexity in a non-linear fashion. In this study, we implement Deep Learning-based networks to determine how gene expression data predicts Cox regression survival in breast cancer. We accomplish this through an algorithm called SALMON (Survival Analysis Learning with Multi-Omics Neural Networks), which aggregates and simplifies gene expression data and cancer biomarkers to enable prognosis prediction. The results revealed improved performance when more omics data were used in model construction. Rather than use raw gene expression values as model inputs, we innovatively use eigengene modules from the result of gene co-expression network analysis. The corresponding high impact co-expression modules and other omics data are identified by feature selection technique, then examined by conducting enrichment analysis and exploiting biological functions, escalated the interpretation of input feature from gene level to co-expression modules level. Our study shows the feasibility of discovering breast cancer related co-expression modules, sketch a blueprint of future endeavors on Deep Learning-based survival analysis. SALMON source code is available at https://github.com/huangzhii/SALMON/.
... The amplifications of 13q, 17p and the deletion of 19q were related to histological grade, and the gains of chromosome 13q was obvious higher in middle-low differentiation than in high differentiation. The regions of chromosome 13q changed were often located in 13q13-21 and 13q33-ter, in which RB1 and BRCA2 genes took part in tumorigenesis in numerous carcinomas (for instance, chronic lymphocytic leukemia, brain malignant glioma, and so on [30,31]. The deletion level of chromosome 19q was higher in high differentiation, thus we supposed that it might be a mark of cancer differentiation. ...
Multiple chromosome aberrations are responsible for tumorigenesis of esophagus squamous cell carcinoma (ESCC). To characterize genetic alterations by comparative genomic hybridization (CGH) and their relation to ESCC, We enrolled 54 members with ESCC from Kazakh's patients. We found that the deletions of 3p (P = 0.032), 17p (P = 0.004), 22q (P = 0.000) and gains of 5p (P = 0.000), 11q (P = 0.000) were significantly correlated with the location of tumors. Losses of 1p (P = 0.005), 3p (P = 0.006), 22q (P = 0.024) and gains of 3q (P = 0.043), 8q (P = 0.038), 18q (P = 0.046) were also found more frequently in patients with larger diameter disease. The loss of 19q (P = 0.005) and gains of l3q (P = 0.045), 18p (P = 0.018) were significantly correlated with pathologic grade. The gain of 7p (P = 0.009) and deletion of 19q (P = 0.018) were seen more frequently in patients with Grade III-IV tumors. Chromosome amplifications in ESCC at 1q (P = 0.008), 7p (P = 0.008), 8q (P = 0.018) and deletions at 3p (P = 0.021), 11q (P = 0.002), 17p (P = 0.012) were related to lymph node metastasis; the gains of 1q (P = 0.026) and 6q (P = 0.017) and the loss of 11q (P = 0.001) were significant in different isoforms of HPV infection. We identified some chromosomes in which the genes were related to the tumorgenesis of ESCC, which may be a theme for future investigation.
... Some randomized controlled trail of rFVIIa in trauma patients reported a trend toward reduced transfusion requirement and mortality [35]. A number of studies have described the development of off-license rFVIIa treatment guidelines in various clinical contexts [30,[36][37][38]. Lack of randomized controlled trials results in practice guidelines based on weak recommendations, however, guidelines implementation improves patients outcome particularly when incorporating factors that are shown to influence outcome [39]. ...
Background and Objectives: Recombinant factor VIIa (rFVIIa) is approved for treatment of inhibitors in hemophilia but has also been used for numerous off-label indications. Type of study: This study aims to validate a modified Biss scoring system in patients who received recombinant factor rFVIIa in Jeddah, Saudi Arabia. Materials and Methods: We included 70 patients who received rFVIIa for off-label indications over 12 months. Characteristics of survivor and non-survivor groups were compared including demographics, laboratory and clinical data. Using a modified Biss prognostic scoring system, based on the original scoring system used by Biss and Hanley, patients were divided into low (<1), intermediate (1-2) and high (≥3) score groups. Results: The mean age of patients was 46.1(±18.6) years. The most common off-label indications for rFVIIa treatment were to control bleeding associated with cardiac surgery (33%) and management of intracranial hemorrhage (18.8%). Forty three patients (61.6%) were at low risk, 20(28.6%) were at intermediate risk, and 7 (10%) were at high risk. Survivors were younger than non-survivors and less likely to have coagulopathy, or renal impairment at the time of treatment. The total prognostic score correlated to survival outcome (P ≤ 0.042); 73.2%, 22%, 4.9% of survivors had a low, intermediate and high score, respectively. Conclusions: Our results suggest that a modified Biss score could help predict survival of patients receiving rFVIIa. Prospective studies are needed to further validate the utility of this scoring system.
... Deletion of this particular region 13q13.3 has been reported in different cancers such as breast cancer [160,161] and lung cancer [162]. Here, this region was reported with one gene DCLK1. ...
Background:
Skin melanocytes can give rise to benign and malignant neoplasms. Discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. However, previous studies have shown that in contrast to benign nevi, melanoma demonstrates pervasive chromosomal aberrations.
Objective:
This substantial difference between melanoma and benign nevi can be exploited to discriminate between melanoma and benign nevi.
Methods:
Array-comparative genomic hybridization (aCGH) is an approach that can be used on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues to assess the entire genome for the presence of changes in DNA copy number. In this study, high resolution, genome-wide single-nucleotide polymorphism (SNP) arrays were utilized to perform comprehensive and detailed analyses of recurrent copy number aberrations in 41 melanoma samples in comparison with 21 benign nevi.
Results:
We found statistically significant copy number gains and losses within melanoma samples. Some of the identified aberrations are previously implicated in melanoma. Moreover, novel regions of copy number alterations were identified, revealing new candidate genes potentially involved in melanoma pathogenesis.
Conclusions:
Taken together, these findings can help improve melanoma diagnosis and introduce novel melanoma therapeutic targets.
... 29 This gene showed no copy number losses in the radiation-related MM cases, but was seen in 17% of the asbestos-related MM cases, a difference that did not meet our difference threshold or p-value cutoff. Loss of 14q is also seen in breast carcinomas that harbor BRCA2 mutations, 30 suggesting that progressive loss of tumor suppressor function involving 14q requires more than one locus for cancer progression; this may be a necessary oncogenic event in some tumors but not a sufficient one. ...
Malignant mesothelioma (MM) is an aggressive tumor arising from mesothelial linings of the serosal cavities. Pleural space is the most common site, accounting for about 80% of cases, while peritoneum makes up the majority of the remaining 20%. While histologically similar, tumors from these sites are epidemiologically and clinically distinct and their attribution to asbestos exposure differs. We compared DNA array-based findings from 48 epithelioid peritoneal MMs and 41 epithelioid pleural MMs to identify similarities and differences in copy number alterations (CNAs). Losses in 3p (BAP1 gene), 9p (CDKN2A) and 22q (NF2) were seen in tumors from both tumor sites, although CDKN2A and NF2 losses were seen at a higher rate in pleural disease (p<0.01). Overall, regions of copy number gain were more common in peritoneal MM, whereas losses were more common in pleural MM, with regions of loss containing known tumor suppressor genes and regions of gain encompassing genes encoding receptor tyrosine kinase pathway members. Cases with known asbestos causation (n=32) were compared with those linked to radiation exposure (n=9). Deletions in 6q, 14q, 17p and 22q, and gain of 17q were seen in asbestos-associated but not radiation-related cases. As reported in post-radiation sarcoma, gains outnumbered losses in radiation-associated MM. The patterns of genomic imbalances suggest overlapping and distinct molecular pathways in MM of the pleura and peritoneum, and that differences in causation (i.e., asbestos vs. radiation) may account for some of these site-dependent differences.
