Porocarcinomas harbor recurrent HRAS-activating mutations and tumor suppressor inactivating mutations

Harms, Paul W.; Hovelson, Daniel H.; Cani, Andi K.; Omata, Kei; Haller, Michaela; Wang, Michael L.; Arps, David P.; Patel, Rajiv M.; Fullen, Douglas R.; Wang, Min; Siddiqui, Javed; Andea, Aleodor A.; Tomlins, Scott A.

doi:10.1016/j.humpath.2015.12.015

Cited by 44 publications

(61 citation statements)

References 33 publications

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“…Targeted next‐generation sequencing confirmed mutations in TP53 , PIK3CA , CDKN2A , RB , ATM , HRAS and HER2 genes, previously described in two smaller series of SAC . In addition, the use of a more extensive NGS panel, targeting 50 cancer‐related genes, allowed us to reveal mutations in further genes such as NRAS , KRAS , MET , FBXW7 and FGFR3 in porocarcinoma, AKT1 in hidradenocarcinoma and APC or FLT3 in PDSAC.…”

Section: Discussionsupporting

confidence: 66%

Identification of potentially druggable molecular alterations in skin adnexal malignancies

Cavalieri

Busico

Capone

et al. 2019

The Journal of Dermatology

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Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histological differentiation towards epithelial adnexa, which lack effective systemic treatments. The aim of this work is to identify any potentially druggable genomic alterations for possible targeted therapies. Cases of primary or recurrent/metastatic (RM) SAC between 2002 and 2014 were identified by searching the institutional cancer registration database. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm diagnosis. Immunohistochemistry was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER2). Targeted next‐generation sequencing (T‐NGS) was performed to identify targetable mutations (panel of 50 genes analyzed by Cancer Hotspot Panel, Ion‐Torrent Personal Genome Machine). Mutational analysis of the PTCH1 gene not present in the T‐NGS panel was assessed by Sanger sequencing. A total of 45 cases with available histological samples were identified (35 primary, 10 RM). The most frequent histological type was porocarcinoma (n = 12). Globally, 14 cases (31%) were AR+ (6/10 RM, 60%; 8/35 primary, 23%). HER2 was shown as 2+ in eight of 42 (19%) cases (2/9 RM, 22%; 6/33 primary, 18%). DNA was adequate for T‐NGS analysis in 25 cases. In the majority of cases (17 cases, 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP.53 (13 cases, 76% of mutated SAC) and PIK3CA (three cases, 18%). The rate of PTCH1 mutation was 30%. These findings support the use of molecular screening in patients with advanced SAC.

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Section: Discussionsupporting

confidence: 66%

Identification of potentially druggable molecular alterations in skin adnexal malignancies

Cavalieri

Busico

Capone

et al. 2019

The Journal of Dermatology

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“…Of the 15 porocarcinoma cases with evaluable staining, three displayed overexpression (Figure C,D), and five displayed diffuse loss (Figure E,F). TP53 mutation data were available for four cases (Table ); of these, overexpression was associated with the dominant negative p.R248Q mutation in one case, and loss was associated with the truncating p.W146X mutation in one case, as previously reported . The remainder of cases with p53 overexpression or loss did not have known TP53 mutational status.…”

Section: Resultsmentioning

confidence: 82%

“…In porocarcinomas, Rb protein loss was present in 9/16 (56%) of cases, of which four displayed focal loss, and five showed diffuse loss (Figure C‐F; Table ). Correlation with RB1 mutational data available for four cases showed that diffuse Rb protein loss correlated with truncating mutations, whereas focal Rb loss was associated with wild type RB1 (Table ).…”

Section: Resultsmentioning

confidence: 98%

“…By database search of the Michigan Medicine Department of Pathology archives, we identified 16 cases of porocarcinoma (Table , Figure ), and further identified 15 consecutive cases of benign poromas (Figure ). Of the porocarcinomas, four were previously evaluated by next generation sequencing and p53 immunohistochemistry …”

Section: Resultsmentioning

confidence: 99%

“…p16 expression was scored as normal (expression in <90% of cells) or overexpressed (expression in >90% of tumor cells). A subset of cases had been previously stained for p53 expression alongside mutation analysis (Table ); these stains were repeated alongside the current cohort, with identical results to those described in the original report. For all markers, the entire tumor present for evaluation was considered when determining the percentage of positive and negative cells.…”

Section: Methodsmentioning

confidence: 99%

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Altered Rb, p16, and p53 expression is specific for porocarcinoma relative to poroma

et al. 2019

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Background Porocarcinomas are rare aggressive carcinomas that harbor tumor suppressor mutations and must be distinguished from benign entities such as poromas. Methods To determine whether altered expression of these genes was diagnostically informative, we examined p53, Rb, and p16 staining patterns in 15 poromas and 16 porocarcinomas. Results Poromas consistently displayed diffuse strong expression of Rb in all but one case that displayed focal loss (1/15, 7%), and no evidence of aberrancy in p53 or p16. Porocarcinomas displayed diffuse or focal loss of Rb expression in 9/16 (56%) cases, diffuse loss or overexpression of p53 in 8/15 (53%), and diffuse loss or overexpression of p16 in 6/14 (43%). Diffuse aberrancy in p53 and Rb expression correlated with tumor mutations in TP53 and RB1, respectively, whereas focal Rb loss was associated with wild type RB1. Diffuse p16 overexpression correlated with Rb loss rather than CDKN2A mutation. For porocarcinomas with all three stains evaluable, 10/13 (77%) displayed aberrancy in at least one marker. Conclusions Our findings suggest that altered p53, p16, and/or Rb expression is relatively specific to porocarcinoma in comparison with poroma. Technical limitations of this panel, including possible focal Rb loss, must be kept in mind, especially in limited samples.

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Serial monitoring of genomic alterations in circulating tumor cells of ER‐positive/HER2‐negative advanced breast cancer: feasibility of precision oncology biomarker detection

et al. 2021

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Nearly all estrogen receptor (ER)‐positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER‐POS breast cancer remain largely unexplored. Whole‐blood (WB) specimens were collected at serial time points from patients with advanced ER‐POS/HER2‐negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch®/DEPArray™ technologies and genomically profiled by targeted single‐cell DNA next‐generation sequencing (scNGS). High‐quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC‐based framework for precision medicine actionability reporting (MI‐CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto‐oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter‐CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real‐time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.

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Porocarcinomas harbor recurrent HRAS-activating mutations and tumor suppressor inactivating mutations

Cited by 44 publications

References 33 publications

Identification of potentially druggable molecular alterations in skin adnexal malignancies

Identification of potentially druggable molecular alterations in skin adnexal malignancies

Altered Rb, p16, and p53 expression is specific for porocarcinoma relative to poroma

Serial monitoring of genomic alterations in circulating tumor cells of ER‐positive/HER2‐negative advanced breast cancer: feasibility of precision oncology biomarker detection

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