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DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features

Lin, Lawrence Hsu; Tran, Ivy; Yang, Yiying; Shen, Guomiao; Miah, Pabel; Cotzia, Paolo; Roses, Daniel; Schnabel, Freya; Darvishian, Farbod; Snuderl, Matija
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.
PMID: 37595637
ISSN: 1530-0285
CID: 5575232

An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma

Davalos, Veronica; Lovell, Claudia D; Von Itter, Richard; Dolgalev, Igor; Agrawal, Praveen; Baptiste, Gillian; Kahler, David J; Sokolova, Elena; Moran, Sebastian; Piqué, Laia; Vega-Saenz de Miera, Eleazar; Fontanals-Cirera, Barbara; Karz, Alcida; Tsirigos, Aristotelis; Yun, Chi; Darvishian, Farbod; Etchevers, Heather C; Osman, Iman; Esteller, Manel; Schober, Markus; Hernando, Eva
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.
PMID: 37015919
ISSN: 2041-1723
CID: 5463692

Associations between TERT promoter mutations and survival in superficial spreading and nodular melanomas in a large prospective patient cohort

Chang, Gregory A; Robinson, Eric; Wiggins, Jennifer M; Zhang, Yilong; Tadepalli, Jyothirmayee S; Schafer, Christine N; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard; Shao, Yongzhao; Osman, Iman; Polsky, David
Survival outcomes in melanoma, and their association with mutations in the telomerase reverse transcriptase (TERT) promoter, remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism, or vary based on 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 AJCC stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (RFS) (HR=2.58, p=0.001), and overall survival (HR=2.47, p=0.029). Patients with the germline variant and TERT-124[C>T] mutant melanomas had significantly shorter RFS than those patients lacking either or both sequence variants (p<0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading compared to 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.
PMID: 35469904
ISSN: 1523-1747
CID: 5205542

Invasive lobular carcinoma with extracellular mucin (ILCEM): clinicopathologic and molecular characterization of a rare entity

Soong, T Rinda; Dillon, Deborah A; Rice-Stitt, Travis L; Wieczorek, Tad John; Baker, Gabrielle M; Darvishian, Farbod; Collins, Laura C; Lester, Susan C; Schnitt, Stuart J; Harrison, Beth T
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.
PMID: 35477749
ISSN: 1530-0285
CID: 5205682

Radar reflector guided axillary surgery in node positive breast cancer patients

Feinberg, Joshua A; Axelrod, Deborah; Guth, Amber; Maldonado, Leonel; Darvishian, Farbod; Pourkey, Nakisa; Goodgal, Jenny; Schnabel, Freya
INTRODUCTION/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.
PMID: 36345879
ISSN: 1745-2422
CID: 5357152

Macrophage density is an adverse prognosticator for ipsilateral recurrence in ductal carcinoma in situ

Darvishian, Farbod; Wu, Yinxiang; Ozerdem, Ugur; Chun, Jennifer; Adams, Sylvia; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Troxel, Andrea B; Schnabel, Freya; Roses, Daniel
INTRODUCTION/BACKGROUND: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:macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.
PMID: 35489232
ISSN: 1532-3080
CID: 5217782

The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

Moubarak, Rana S; de Pablos-Aragoneses, Ana; Ortiz-Barahona, Vanessa; Gong, Yixiao; Gowen, Michael; Dolgalev, Igor; Shadaloey, Sorin A A; Argibay, Diana; Karz, Alcida; Von Itter, Richard; Vega-Sáenz de Miera, Eleazar Carmelo; Sokolova, Elena; Darvishian, Farbod; Tsirigos, Aristotelis; Osman, Iman; Hernando, Eva
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 TGFβ 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.
PMID: 35179962
ISSN: 2375-2548
CID: 5163652

Tubulopapillary Carcinoma of the Breast: A Distinct Morphologic Entity with Molecular and Immunohistochemical Analysis [Meeting Abstract]

Salama, Abeer; Schwartz, Christopher; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Jour, George; Park, Kyung; Snuderl, Matija; Cotzia, Paolo; Darvishian, Farbod
ISSN: 0023-6837
CID: 5243152

Tubulopapillary Carcinoma of the Breast: A Distinct Morphologic Entity with Molecular and Immunohistochemical Analysis [Meeting Abstract]

Salama, Abeer; Schwartz, Christopher; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Jour, George; Park, Kyung; Snuderl, Matija; Cotzia, Paolo; Darvishian, Farbod
ISSN: 0893-3952
CID: 5243282

Breast cancer risk factors and circulating anti-Müllerian hormone concentration in healthy premenopausal women

Clendenen, Tess V; Ge, Wenzhen; Koenig, Karen L; Afanasyeva, Yelena; Agnoli, Claudia; Bertone-Johnson, Elizabeth; Brinton, Louise A; Darvishian, Farbod; Dorgan, Joanne F; Eliassen, A Heather; Falk, Roni T; Hallmans, Göran; Hankinson, Susan E; Hoffman-Bolton, Judith; Key, Timothy J; Krogh, Vittorio; Nichols, Hazel B; Sandler, Dale P; Schoemaker, Minouk J; Sluss, Patrick M; Sund, Malin; Swerdlow, Anthony J; Visvanathan, Kala; Liu, Mengling; Zeleniuch-Jacquotte, Anne
CONTEXT/BACKGROUND:In a previous study we reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE:Assess whether risk factors for breast cancer are correlates of AMH concentration. DESIGN/METHODS:Cross-sectional. PARTICIPANTS/METHODS:3831 healthy premenopausal women (aged 21-57, 87% aged 35-49). SETTING/METHODS:Ten cohort studies, general population. RESULTS:Adjusting for age and cohort, we observed positive associations of AMH with age at menarche (p<0.0001) and parity (p=0.0008), and an inverse association with hysterectomy/partial oophorectomy (p=0.0008). Compared to women of normal weight (BMI 18.5-24.9 kg/m 2, AMH was lower (relative geometric mean difference 27%, p<0.0001) among women who were obese (BMI>30). Current oral contraceptive use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, p<0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, p=0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40/≥40), associations of AMH with BMI and oral contraceptives 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 women ≥40 (p-interaction<0.05). CONCLUSION/CONCLUSIONS:This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and suggests that most of the associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
PMID: 34157104
ISSN: 1945-7197
CID: 4918342