ABSTRACT
Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that α-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding α-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growth in vivo and in vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon α-2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that α-2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors.
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AIMS: We investigated key signalling pathways' activity and mutational status of early-stage breast carcinomas with low and intermediate 21-gene recurrence score (RS) to identify molecular features that may predict recurrence. METHODS: This is a retrospective case-control study of 18 patients with recurrent breast carcinoma with low and intermediate 21-gene RS (<25) and control group of 15 non-recurrent breast cancer patients. DNA and mRNA were extracted from tumour tissue. mRNA expression of genes involved in oestrogen receptor (ER), androgen receptor (AR), PI3K and MAPK signalling pathways was measured by real-time quantitative reverse transcription-qPCR (OncoSIGNal G4 test, InnoSIGN). Tumour mutational landscape was assessed by targeted DNA sequencing (Oncomine Precision Assay). RESULTS: There were no statistical differences between the groups' demographic and clinicopathological characteristics. PI3K pathway showed significantly higher activity in cases compared with controls (p=0.0014). Receiver operating characteristic curve analysis showed an area under the curve of 0.79 for PI3K pathway activity in the prediction of recurrent disease in low and intermediate 21-gene RS breast cancer. There was no difference in ER, AR and MAPK pathway activity. PIK3CA alterations were the most common driver mutations, but no difference was found between the groups (p=0.46) and no association with PI3K pathway activity (p=0.86). Higher Ki67 gene expression was associated with recurrences (p=0.042) CONCLUSION: Increased PI3K pathway activity, independent of PIK3CA mutations, may play a role in the recurrence of early-stage breast cancer with low and intermediate 21-gene RS. Pathway analysis can help to identify high-risk patients in this setting.
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Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.
Subject(s)
DNA Methylation , Triple Negative Breast Neoplasms , Humans , Middle Aged , Aged , BRCA1 Protein/genetics , Triple Negative Breast Neoplasms/pathology , Ki-67 Antigen/metabolism , Phosphatidylinositol 3-Kinases/genetics , BRCA2 Protein/genetics , Epigenesis, GeneticABSTRACT
Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to-mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 - isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Cell Line, Tumor , Melanoma/pathology , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Epithelial-Mesenchymal Transition/genetics , Epigenesis, Genetic , Protein Isoforms/genetics , Protein Isoforms/metabolism , Gene Expression Regulation, Neoplastic , COUP Transcription Factor II/metabolismABSTRACT
BACKGROUND: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. METHODS: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. RESULTS: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. CONCLUSIONS: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.
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INTRODUCTION: In patients with non-palpable breast cancer, the availability of wireless localization techniques facilitates removal of the target lesion. One such technique uses a radar reflector for localization (RRL). This study evaluates the feasibility and effectiveness of RRL to guide excision of axillary lymph nodes in patients with node-positive breast cancer. METHODS: Our Breast Cancer Database was queried for patients diagnosed with breast cancer, between 5/2017 and 10/2021, who underwent preoperative placement of a radar reflector into a biopsy proven axillary lymph node. Clinicopathologic data were reported using descriptive statistics. RESULTS: Twenty patients underwent preoperative placement of a radar reflector into the axilla. Intraoperatively, the clip and radar reflector were successfully removed in all patients. Among the 10 patients treated with NAC, 5 patients achieved an axillary pathologic complete response (pCR) and were spared a complete axillary lymph node dissection (cALND). Among the entire cohort, RRL resulted in a 53% reduction in the number of lymph nodes removed. CONCLUSIONS: Wireless localization of axillary lymph nodes is safe and feasible. The technique ensures excision of biopsy proven positive axillary lymph nodes and enables a targeted approach to assessing the axilla, both in the setting of NAC and upfront surgery.
Subject(s)
Breast Neoplasms , Humans , Female , Axilla/pathology , Breast Neoplasms/diagnosis , Sentinel Lymph Node Biopsy/methods , Radar , Lymphatic Metastasis , Neoadjuvant Therapy , Lymph Nodes/surgery , Lymph Nodes/pathology , Lymph Node Excision/methods , Neoplasm StagingABSTRACT
Survival outcomes in melanoma and their association with mutations in the telomerase reverse transcriptase gene TERT promoter remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism or vary on the basis of melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype, and CNS involvement. In a multivariable model controlling for the American Joint Committee on Cancer stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (hazard ratio = 2.58, P = 0.001) and overall survival (hazard ratio = 2.47, P = 0.029). Patients with the germline variant and TERT-124[C>T]-mutant melanomas had significantly shorter recurrence-free survival than those lacking either or both sequence variants (P < 0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading than in nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF, or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.
Subject(s)
Melanoma , Telomerase , Humans , Melanoma/pathology , Mutation , Prospective Studies , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms , Telomerase/genetics , Telomerase/metabolism , Melanoma, Cutaneous MalignantABSTRACT
Invasive lobular carcinoma with extracellular mucin (ILCEM) is a rare histologic subtype of breast cancer. Little is known about the pathologic or genomic signatures that distinguish ILCEM from classic invasive lobular carcinoma (ILC) or mucinous carcinoma. We studied 17 breast cancers with lobular morphology and extracellular mucin. Thirteen tumors with sufficient tissue for DNA extraction were analyzed by a next generation sequencing (NGS) assay that interrogates 447 genes for mutations and copy number variations (CNVs). Median patient age was 66 yrs (range: 31-77 yrs). Sixteen patients presented with masses, 7 of which were >2 cm. Seven patients had lymph node metastases. The cases of ILCEM were moderately (n = 13) or poorly differentiated (n = 4), frequently exhibiting variant morphology that has not been previously described or emphasized, including grade 3 nuclei (n = 11), diffuse signet ring cells (n = 10), solid growth (n = 4), tumor necrosis (n = 3) or apocrine features (n = 2). All tumors showed absent or reduced membranous E-cadherin expression. Concurrent lobular carcinoma in situ (LCIS) was seen in 11/17 cases, 1 of which was a striking example of signet ring cell LCIS with extracellular mucin. Receptor profiles were ER+/HER2- (n = 15) and ER+/HER2+ (n = 2). With a median follow-up of 83.5 months (range: 3-171 months) in 12 patients with available information, 8 patients had recurrences resulting in 4 cancer-related deaths. The most common CNVs were 16q loss (n = 11) and 1q gain (n = 9). CDH1 gene-level alterations were detected in all but one case, including frameshift (n = 7), nonsense (n = 2), and donor splice site (n = 1) mutations and indels (n = 2). Recurrent mutations were also seen in PIK3CA (n = 3), POLQ (n = 3), TP53 (n = 3), ERBB3 (n = 3), ERBB2 (n = 2), and RUNX1 (n = 2). Genes with recurrent amplifications included GATA3 (n = 4), FOXA1 (n = 3), CCND1 (n = 2). Our data highlights ILCEM as a distinct variant of ILC that often presents with higher-grade and variant morphologic features and is associated with an aggressive clinical course. NGS data support an overall lobular-type molecular profile and reveal potentially targetable alterations in a subset of cases with recurrence.
Subject(s)
Breast Carcinoma In Situ , Breast Neoplasms , Carcinoma, Lobular , Adult , Aged , Breast Carcinoma In Situ/pathology , Breast Neoplasms/pathology , Cadherins/genetics , Carcinoma, Lobular/pathology , Class I Phosphatidylinositol 3-Kinases/genetics , Core Binding Factor Alpha 2 Subunit/genetics , DNA , DNA Copy Number Variations , Female , Humans , Middle Aged , MucinsABSTRACT
INTRODUCTION: There is evidence that supports the association of dense tumor infiltrating lymphocyte (TILs) with an increased risk of ipsilateral recurrence in ductal carcinoma in situ (DCIS). However, the association of cellular composition of DCIS immune microenvironment with the histopathologic parameters and outcome is not well understood. METHODS: We queried our institutional database for patients with pure DCIS diagnosed between 2010 and 2019. Immunohistochemical studies for CD8, CD4, CD68, CD163, and FOXP3 were performed and evaluated in the DCIS microenvironment using tissue microarrays. Statistical methods included Fisher's exact test for categorical variables and the two-sample t-test or the Wilcoxon Rank-Sum test for continuous variables. RESULTS: The analytic sample included 67 patients. Median age was 62 years (range = 53 to 66) and median follow up was 6.7 years (range = 5.3 to 7.8). Thirteen patients had ipsilateral recurrence. Of all the clinicopathologic variables, only the DCIS size and TIL density were significantly associated with recurrence (p = 0.023 and 0.006, respectively). After adjusting for age and TIL density, only high CD68 (>50) and high CD68/CD163 ratio (>0.46) correlated with ipsilateral recurrence (p = 0.026 and 0.013, respectively) and shorter time to recurrence [hazard ratio 4.87 (95% CI: 1.24-19, p = 0.023) and 10.32 (95% CI: 1.34-80, p = 0.025), respectively]. CONCLUSIONS: In addition to DCIS size and TIL density, high CD68+ tumor-associated macrophages predict ipsilateral recurrence in DCIS. High CD68+ macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.
Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Aged , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Female , Humans , Lymphocytes, Tumor-Infiltrating , Macrophages , Middle Aged , Neoplasm Recurrence, Local/pathology , Prognosis , Tumor MicroenvironmentABSTRACT
The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified Plant Homeodomain Finger protein 8 (PHF8), a histone demethylase of the Jumonji C protein family, as a previously unidentified prometastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro and increases dissemination but not subcutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFß signaling pathway and, as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.
Subject(s)
Histone Demethylases , Melanoma , Cell Proliferation , Epigenesis, Genetic , Histone Demethylases/genetics , Histone Demethylases/metabolism , Homeodomain Proteins/genetics , Humans , Melanoma/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
CONTEXT: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE: This study assessed whether risk factors for breast cancer are correlates of AMH concentration. METHODS: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population. RESULTS: Adjusting for age and cohort, AMH positively associated with age at menarche (Pâ <â 0.0001) and parity (Pâ =â 0.0008) and inversely associated with hysterectomy/partial oophorectomy (Pâ =â 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, Pâ <â 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, Pâ <â 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, Pâ =â 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to womenâ ≥40 (P-interactionâ <â 0.05). CONCLUSION: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
Subject(s)
Anti-Mullerian Hormone/blood , Breast Neoplasms/blood , Premenopause/blood , Adult , Aging/blood , Biomarkers , Body Mass Index , Breast Diseases/blood , Cohort Studies , Cross-Sectional Studies , Female , Humans , Middle Aged , Ovarian Reserve , Pregnancy , Risk FactorsABSTRACT
Primary mucinous cystadenocarcinoma of the breast is a rare neoplasm with few reports in the literature. Here, we report for the first time a comprehensive genetic profile of a primary mucinous cystadenocarcinoma of the breast, using next-generation sequencing 580 cancer-associated gene panel. Mutations in TP53, RB1, and BAP1 were identified. The findings suggest that this tumor is driven mostly by abnormalities in tumor suppressor genes, primarily involved in cell cycle control and chromatin remodeling. Molecular characterization of additional primary mucinous cystadenocarcinomas of the breast is warranted and might provide information related to its biology and behavior.
Subject(s)
Breast Neoplasms , Cystadenocarcinoma, Mucinous , Breast , Breast Neoplasms/genetics , Cystadenocarcinoma, Mucinous/genetics , Female , Genetic Profile , Humans , Mutation , Tumor Suppressor Proteins , Ubiquitin ThiolesteraseABSTRACT
Encapsulated papillary carcinomas (EPCs) of the breast are a unique variant of papillary carcinoma confined to a cystic space with absent or attenuated myoepithelial cell layer. Although staged as an in situ lesion, it can be associated with invasive ductal carcinoma (IDC). We sought to compare the genomic characteristics of pure EPC and EPC with associated invasive carcinoma (EPCi) at the genomic level. All cases of EPCi harbored recurrent hotspot mutations in PIK3CA. PIK3CA, KMT2A, and CREBBP deleterious somatic events were found across both tumor groups, irrespective of invasion status. At the whole transcriptomic level, EPCi cases displayed remarkably similar mRNA profiles when compared to EPC. When EPCi cases were compared with their corresponding IDC, despite significant overlap, we identified differential gene expression in 39 genes with enrichment of multiple pathways including extracellular matrix regulation, cell adhesion, and collagen fibril organization. Despite morphologic, genotypic, and transcriptomic overlap between pure EPC and EPCi, the latter tumors are likely advanced lesions with PIK3CA activating mutations and enrichment of stromal-related genes implicated in the switch to IDC.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Carcinoma, Papillary/genetics , Carcinoma, Papillary/pathology , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Female , Humans , Male , Middle Aged , Mutation , Retrospective StudiesABSTRACT
Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.
Subject(s)
Diagnosis, Computer-Assisted , Image Interpretation, Computer-Assisted , Lymphocytes, Tumor-Infiltrating/immunology , Machine Learning , Melanoma/immunology , Microscopy , Skin Neoplasms/immunology , Adult , Aged , Automation, Laboratory , Biopsy , Databases, Factual , Disease Progression , Female , Humans , Lymphocyte Count , Male , Melanoma/mortality , Melanoma/pathology , Melanoma/therapy , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Predictive Value of Tests , Progression-Free Survival , Reproducibility of Results , Retrospective Studies , Risk Assessment , Risk Factors , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Tumor Microenvironment/immunologyABSTRACT
The management of intraductal papilloma (IDP) diagnosed on core needle biopsy (CNB) is controversial due to the variable upgrade rates to breast carcinoma (BC) on subsequent surgical excision reported in the literature. The purpose of our study was to investigate the upgrade rate of IDP diagnosed on CNB to BC in subsequent surgical excision and the impact of clinical, pathologic, and radiologic variables. This is a retrospective cohort of all women who had a diagnosis of IDP on a CNB between 2005 and 2018 in a tertiary academic center with subsequent surgical excision. Upgrade was defined as ductal carcinoma in situ (DCIS) and invasive carcinoma on surgical excision. Statistical analyses included Pearson's chi-square, Wilcoxon rank-sum, and logistic regression. A total of 216 women with IDP in a CNB were included. Nineteen patients (8.8%) upgraded to BC in the overall cohort, including 14 DCIS and 5 invasive carcinomas. An upgrade rate of 27% was found in atypical IDP (14 of 51 cases), while only 3% of pure IDP upgraded to BC (5 of 165 cases). Older age (>53 years) at the time of biopsy (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.01-1.09, p = 0.027) and concomitant atypical ductal hyperplasia (ADH) (OR = 9.69, 95% CI = 3.37-27.81, p < 0.0001) were significantly associated with upgrade. Our results support surgical excision of IDP on CNB when associated with ADH or diagnosed in women aged older than 53 years. The low surgical upgrade rate of 3% for pure IDP on CNB in younger women should be part of the management discussion.
Subject(s)
Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Papilloma, Intraductal/pathology , Papilloma, Intraductal/surgery , Adult , Aged , Aged, 80 and over , Biopsy/methods , Biopsy, Large-Core Needle/methods , Breast Neoplasms/surgery , Carcinoma, Intraductal, Noninfiltrating/surgery , Female , Humans , Hyperplasia/pathology , Middle Aged , Papilloma, Intraductal/diagnosis , Retrospective Studies , Young AdultABSTRACT
Dermal invasion is a hallmark of malignant melanoma. Although the molecular alterations that drive the progression of primary melanoma to metastatic disease have been studied extensively, the early progression of noninvasive primary melanoma to an invasive state is poorly understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase A1 drives tumor invasion. Transcriptomic analysis of ribosomal protein S6 kinase A1-activated tumors identified metabolic changes, including up-regulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator activated receptor γ coactivator (PGC)-1α, has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens, PGC1α protein expression was found to be positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species scavenger receptor class A member 3. PGC1α depletion modulated cellular processes associated with primary melanoma growth and invasion, including oxidative stress. These results support a role for PGC1α in mediating glutamine-driven oxidative phosphorylation to facilitate the invasive growth of primary melanoma.
Subject(s)
Melanoma/metabolism , Melanoma/pathology , Oxidative Phosphorylation , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Animals , Heterografts , Humans , Neoplasm Invasiveness , ZebrafishABSTRACT
Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, TERT-124C>T, and TERT-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%), and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT-124C>T and TERT-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one had different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in at least one of their metastases. Overall, we identified mutational heterogeneity in 18 of 99 patients (18%). These results suggest that some primary melanomas may be composed of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.
Subject(s)
GTP Phosphohydrolases/genetics , Melanoma/genetics , Membrane Proteins/genetics , Neoplasms, Second Primary/genetics , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/genetics , Telomerase/genetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , DNA Mutational Analysis , Drug Resistance, Neoplasm/genetics , Female , Genetic Heterogeneity , Humans , Longitudinal Studies , Male , Melanoma/mortality , Melanoma/secondary , Middle Aged , Mutation , Neoplasms, Second Primary/drug therapy , Neoplasms, Second Primary/mortality , Neoplasms, Second Primary/pathology , Prospective Studies , Skin/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/mortality , Skin Neoplasms/pathologyABSTRACT
Current guidelines recommend sentinel lymph node biopsy (SLNB) for patients undergoing mastectomy for a preoperative diagnosis of ductal carcinoma in situ (DCIS). We examined the factors associated with sentinel lymph node positivity for patients undergoing mastectomy for a diagnosis of DCIS on preoperative core biopsy (PCB). The Institutional Breast Cancer Database was queried for patients with PCB demonstrating pure DCIS followed by mastectomy and SLNB from 2010 to 2018. Patients were divided according to final pathology (DCIS or invasive cancer). Clinico-pathologic variables were analyzed using Pearson's chi-squared, Wilcoxon Rank-Sum and logistic regression. Of 3145 patients, 168(5%) had pure DCIS on PCB and underwent mastectomy with SLNB. On final mastectomy pathology, 120(71%) patients had DCIS with 0 positive sentinel lymph nodes (PSLNs) and 48(29%) patients had invasive carcinoma with 5(10%) cases of ≥1 PSLNs. Factors positively associated with upstaging to invasive cancer in univariate analysis included age (P = .0289), palpability (P < .0001), extent of disease on imaging (P = .0121), mass on preoperative imaging (P = .0003), multifocality (P = .0231) and multicentricity (P = .0395). In multivariate analysis, palpability (P = .0080), extent of disease on imaging (P = .0074) and mass on preoperative imaging (P = .0245) remained significant (Table 2). In a subset of patients undergoing mastectomy for DCIS with limited disease on preoperative evaluation, SLNB may be omitted as the risk of upstaging is low. However, patients who present with clinical findings of palpability, large extent of disease on imaging and mass on preoperative imaging have a meaningful risk of upstaging to invasive cancer, and SLNB remains important for management.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Intraductal, Noninfiltrating , Sentinel Lymph Node , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Intraductal, Noninfiltrating/surgery , Female , Humans , Lymph Nodes/diagnostic imaging , Lymph Nodes/surgery , Mastectomy , Sentinel Lymph Node/diagnostic imaging , Sentinel Lymph Node/surgery , Sentinel Lymph Node BiopsyABSTRACT
CONTEXT.: Bilateral mastectomy for chest masculinization is one of the gender-affirming procedures for transmasculine individuals. OBJECTIVE.: To optimize gross handling protocols and assess histopathologic findings in transmasculine breast tissue specimens. DESIGN.: We identified all gender-affirming mastectomies from 2015 to 2018. We sequentially identified reduction mammoplasty (RM) cases for macromastia from the same period as control. Significant findings were defined as atypical ductal or lobular hyperplasia (ADH, ALH), ductal or lobular carcinoma in situ (DCIS, LCIS), or invasive carcinoma. RESULTS.: Significant findings were present in 6 of 211 gender-affirming mastectomies (2.8%) as follows: ADH (n = 5) and LCIS together with ALH (n = 1). By comparison, 19 of 273 RM specimens (7%) yielded significant findings as follows: ALH (n = 11), ADH (n = 4), LCIS (n = 2), DCIS (n = 1), and invasive lobular carcinoma (n = 1). In the gender-affirming group, 142 transmen underwent androgen therapy before surgery, of whom 2 had significant pathologic findings. Thirty and 41 individuals had a family history of breast cancer in the gender-affirming and RM group, of whom 1 and 3 individuals had significant pathologic findings, respectively. CONCLUSIONS.: Our study demonstrates that we handle transmasculine mastectomy specimens by examining 2.8 times more slides on average than for RMs, with a 2.5 times lower rate of significant pathologic findings. Prior family history of breast cancer or the use of androgen therapy before surgery in gender-affirming individuals did not increase the risk of identifying significant breast lesions. We recommend submitting 4 tissue blocks per mastectomy for individuals undergoing gender-affirming breast surgery.
Subject(s)
Breast Carcinoma In Situ/pathology , Breast Neoplasms/pathology , Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma/pathology , Mastectomy , Sex Reassignment Procedures , Transsexualism/therapy , Adult , Biopsy , Breast/surgery , Databases, Factual , Female , Humans , Male , Neoplasm Invasiveness , Predictive Value of Tests , Retrospective Studies , Transgender Persons , Transsexualism/pathology , Transsexualism/physiopathology , Young AdultABSTRACT
Salivary gland secretory carcinoma, also termed mammary analogue secretory carcinoma (MASC), is a recently described salivary gland neoplasm with characteristic histomorphologic findings similar to those of secretory carcinoma of the breast and harboring recurrent ETV6-NTRK3 fusions. Recent findings have expanded the molecular profile of salivary gland secretory carcinoma to include multiple novel ETV6 fusion partners, including RET, MET, and MAML3. Here, we report a case of cystic MASC with cribriform and papillary histology harboring two gene fusions, ETV6-RET and EGFR-SEPT14, identified by targeted RNA sequencing. The presence of the rearrangements was confirmed by FISH, RT-PCR, and Sanger sequencing. This is the first EGFR-SEPT14 fusion reported in secretory carcinoma as a single event or in association with an ETV6 rearrangement. This finding adds to the expanding molecular profile of this tumor entity, and may translate into novel treatment strategies.