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A molecular comparison of intraductal carcinoma of the prostate, associated invasive high grade prostatic carcinoma, and lymph node metastases by copy number alteration analysis [Meeting Abstract]

Park, K; Robinson, B; Ho, M; Viswanathan, K; Gogineni, S; Miguel, Mosquera J; Barbieri, C; Lotan, T; Loda, M; Mathew, S; Borczuk, A; Khani, F
Background: Intraductal carcinoma of the prostate (IDC-P) is considered a harbinger of aggressive disease and is associated with poor clinical prognosis. It is believed to represent retrograde spread of high grade invasive carcinoma into the prostatic ductular system, although there is minimal molecular evidence to support this theory. We aimed to further study the molecular evolution of IDC-P and how it relates to invasive carcinoma and tumor metastases.
Design(s): Radical prostatectomy specimens where the dominant tumor nodule had an abundant IDC-P component (>20%) were identified. Cases were reviewed by GU pathologists to annotate areas of IDC-P and high grade (> Grade Group 3) invasive carcinoma (HGIC) in ten selected cases. Five cases also had lymph node metastases. DNA was extracted from each macrodissected area and subjected to copy number alteration (CNA) analysis using the OncoScan Assay (Affymetrix). CNA was performed using the Oncoscan Nexus Express software v3.0. FISH was utilized to validate particular key findings with centromeric probes for chromosomes 8, 10, and 12.
Result(s): Similar 8p and 10q losses were seen in both the IDC-P and high grade invasive carcinoma in all 10 cases, and 8q gains were also seen in both areas in 7 cases. In 3 of 10 cases, the IDC-P component showed copy number gains spanning the entire genome in the regions without chromosomal losses, and in one of these cases, the HGIC area showed similar whole genome gains. In addition, those non-amplified regions of chromosomal loss are common to the HGIC and IDC-P components, including both deletion and uniparental disomy. In 2 of 5 cases, the lymph node metastases also showed a copy number profile that was more similar to IDC-P than it was to HGIC, including one case with whole genome gain. Whole genome gains were further validated by FISH, which showed a mixed population of cells containing a range of 2-5 copies of each of the selected chromosomes.
Conclusion(s): IDC-P and invasive high grade carcinoma are clonally related, as evidenced by similar focal chromosomal gains and losses. Whole genome gains are seen in IDC-P, and share the same loss pattern with HGIC. This suggests a clonal evolution from invasive carcinoma to IDC-P in some cases. The copy number alteration pattern of the lymph node metastases is sometimes more similar to IDC-P than it is to HGIC, suggesting that the tumor clones present within IDC-P have metastatic potential
EMBASE:631877206
ISSN: 1530-0285
CID: 4472692

Concordance of p53 immunohistochemistry and tp53 mutation status in endometrial cancer [Meeting Abstract]

Da, Cruz Paula A; DeLair, D; Fix, D; Soslow, R; Park, K; Chiang, S; Reis-Filho, J; Zehir, A; Murali, R; Makker, V; Cadoo, K; Mueller, J; Leitao, M; Abu-Rustum, N; Aghajanian, C; Weigelt, B
Background: For the clinical identification of the four molecular subtypes of endometrial cancer (EC), which were originally identified using whole-exome sequencing, surrogates employing immunohistochemistry (IHC) have been implemented. In this surrogate, p53 IHC is used to identify 'copy-number high'/ p53 abnormal ECs. We sought to define the concordance of p53 IHC and TP53 mutation status in ECs.
Design(s): Patients with newly diagnosed primary EC were prospectively consented to an IRB-approved protocol. ECs were subjected to p53 and DNA mismatch repair (MMR) protein IHC and to massively parallel sequencing targeting 410-468 cancer-related genes. ECs were classified based on POLE mutation status and MMR and p53 IHC into the four molecular subtypes: POLE (ultramutated), MMRdeficient, copy-number low (endometrioid) and copy-number high (serous-like). Concordance between p53 IHC and somatic TP53 mutation status was defined using Cohen's Kappa.
Result(s): 175 ECs were included in this study (116 endometrioid, 17 serous, 11 carcinosarcoma, 13 mixed, 6 clear cell, 7 dedifferentiated, 5 other). 41 (23%) ECs demonstrated aberrant p53 expression by IHC, and of these 36 (88%) harbored a somatic TP53 mutation (Table). Of the 134 ECs with normal/ wild-type p53 protein expression by IHC, the majority of ECs (115; 86%) were molecularly concordant and did not harbor a somatic TP53 mutation (Table). The agreement between the two methods was 151/175 (86%), with a Kappa of 0.726 (good agreement). The sensitivity and specificity of p53 IHC for the detection of pathogenic TP53 mutations was 66% and 96%, respectively. In total, there were 24 (14%) discrepant cases, which had aberrant p53 IHC in the absence of a TP53 mutation (n=5) or a TP53 mutation but normal p53 protein expression patterns (n=19). Of the 19 TP53-mutant ECs with normal p53 IHC, 10 harbored nonpathogenic TP53 mutations, 3 harbored subclonal TP53 hotspot mutations, 3 had subclonal TP53 loss of function mutations, and only 3 had clonal TP53 hotspot mutations (Table). Discrepancies were primarily observed in ECs of MMR-deficient (9/19) or POLE (4/19) EC subtypes. (Table presented)
Conclusion(s): Our findings demonstrate a good concordance between p53 IHC and TP53 mutation status in EC. p53 IHC is a specific and fairly sensitive surrogate for pathogenic TP53 mutations. The type and clonality of TP53 mutations explain the vast majority of discrepancies between sequencing and IHC assessment of TP53
EMBASE:631880007
ISSN: 1530-0285
CID: 4472722

Can Gleason Grade be Reliably Assigned Based on the Perineural Focus of Adenocarcinoma? [Meeting Abstract]

Chen, Fei; Isaila, Bogdan; Parimi (Parini), Vamsi; Ren, Qinghu; Park, Kyung; Huang, Hongying; Deng, Fangming; Melamed, Jonathan
ISI:000478081101277
ISSN: 0023-6837
CID: 4048352

Integrated Expression (Chromogenic in situ Hybridization) of Long Noncoding RNAs (LncRNAs) Segregate Low Grade from Clinically Significant Prostate Cancer [Meeting Abstract]

Parimi (Parini), Vamsi; Xia, Yuhe; Mezzano, Valeria; Vasudevaraja, Varshini; Selvaraj, Shanmugapriya; Loomis, Cynthia; Moreira, Andre; Lee, Peng; Levy, David; Park, Kyung; Huang, Hongying; Ren, Qinghu; Deng, Fangming; Melamed, Jonathan
ISI:000478081101389
ISSN: 0023-6837
CID: 4048382

Expanding Therapeutic Options for Patients with Lung Adenocarcinomas Using Oncomine Comprehensive Panel [Meeting Abstract]

Park, Kyung; Tran, Hung; Feng, Xiaojun; Rubin, Marka; Fernandes, Helen
ISI:000393724402333
ISSN: 0023-6837
CID: 3133682

Expanding Therapeutic Options for Patients with Lung Adenocarcinomas Using Oncomine Comprehensive Panel [Meeting Abstract]

Park, Kyung; Tian, Hung; Feng, Xiaojun; Rubin, Mark A.; Fernandes, Helen
ISI:000394467302425
ISSN: 0893-3952
CID: 3133702

KRAS Mutation Is Highly Prevalent and Predicts Recurrence in Patients with Primary Invasive Mucinous Adenocarcinoma of the Lung [Meeting Abstract]

Kemel, Mohamed K.; Narula, Navneet; Park, Kyung; Stiles, Brendon M.; Port, Jeffrey L.; Fernandes, Helen; Altorki, Nasser K.
ISI:000394467302509
ISSN: 0893-3952
CID: 3150752

KRAS Mutation Is Highly Prevalent and Predicts Recurrence in Patients with Primary Invasive Mutinous Adenocarcinoma of the Lung [Meeting Abstract]

Kamel, Mohamed K.; Narula, Navneet; Park, Kyung; Stiles, Brendon M.; Port, Jeffrey L.; Fernandes, Helen; Altorki, Nasser K.
ISI:000393724402418
ISSN: 0023-6837
CID: 3151812

Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models

Pisapia, David J; Salvatore, Steven; Pauli, Chantal; Hissong, Erika; Eng, Ken; Prandi, Davide; Sailer, Verena-Wilbeth; Robinson, Brian D; Park, Kyung; Cyrta, Joanna; Tagawa, Scott T; Kossai, Myriam; Fontugne, Jacqueline; Kim, Robert; Sigaras, Alexandros; Rao, Rema; Pancirer, Danielle; Faltas, Bishoy; Bareja, Rohan; Molina, Ana M; Nanus, David M; Rajappa, Prajwal; Souweidane, Mark M; Greenfield, Jeffrey; Emde, Anne-Katrin; Robine, Nicolas; Elemento, Olivier; Sboner, Andrea; Demichelis, Francesca; Beltran, Himisha; Rubin, Mark A; Mosquera, Juan Miguel
Purpose/UNASSIGNED:Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types. Materials and Methods/UNASSIGNED:One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts. Results/UNASSIGNED:in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates. Conclusion/UNASSIGNED:A next-generation sequencing-based autopsy program in conjunction with a pre-mortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.
PMCID:5761727
PMID: 29333526
ISSN: 2473-4284
CID: 3061122

Molecular Characterization of Invasive Mucinous Adenocarcinomas of the Lung [Meeting Abstract]

Park, Kyung; Subramaniyam, Shivakwnar; Jessurun, Jose; Fernandes, Helen; Narula, Navneet
ISI:000370302503374
ISSN: 0893-3952
CID: 3150732