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Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

ABSTRACT: Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation.MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258-66. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1197.

SUBMITTER: Mehra R

PROVIDER: S-EPMC5096979 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

Mehra Rohit R Vats Pankaj P Cieslik Marcin M Cao Xuhong X Su Fengyun F Shukla Sudhanshu S Udager Aaron M AM Wang Rui R Pan Jincheng J Kasaian Katayoon K Lonigro Robert R Siddiqui Javed J Premkumar Kumpati K Palapattu Ganesh G Weizer Alon A Hafez Khaled S KS Wolf J Stuart JS Sangoi Ankur R AR Trpkov Kiril K Osunkoya Adeboye O AO Zhou Ming M Giannico Giovanna G McKenney Jesse K JK Dhanasekaran Saravana M SM Chinnaiyan Arul M AM

Cancer discovery 20160907 11

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly im ...[more]

PMID: 27604489

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Project description:BACKGROUND:Mucinous tubular and spindle-cell carcinoma (MTSCC) is a rare kidney cancer subtype with limited cases reported in the literature. We report on outcomes of 25 patients with this variant who were managed at our institution. MATERIALS AND METHODS:The institution database was queried, and clinical data extracted for patients with MTSCC. Molecular features examined included next-generation sequencing with Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets and allele-specific copy number analysis using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm in a subset of patients. RESULTS:All patients underwent primary tumor-directed therapy (nephrectomy = 23, cryoablation = 2). Metastases were diagnosed in 6 patients (24%), 3 (12%) of whom had de novo metastatic disease. Five of 6 patients with metastatic disease had high-grade histological features compared with 0 of 19 nonmetastatic patients (83% vs. 0%; P < .001, Fisher exact test). Three-year overall survival from diagnosis was 84.8% (95% confidence interval, 59.6-94.9) with a median follow-up time of 3.9 years (range, 1 month to 10.3 years). Three deaths occurred, all from metastatic disease. Four patients received systemic therapy with time to treatment failure ?6 months across different agents with the exception of 1 patient with prolonged response with sunitinib treatment (30.6 months). The most frequent molecular alterations were neurofibromin 2 mutations (n = 2; 40%), germline alterations (n = 2; 40%) including checkpoint kinase 2 and BRCA2 DNA repair associated mutations, multiple chromosomal copy number losses, and mismatch repair deficiency in 1 patient. CONCLUSION:MTSCC is characterized by localized tumors treated successfully with primary tumor-directed therapy. However, patients with high-grade histological features were more likely to develop metastatic disease with limited responses to standard therapies.

Project description:Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma with characteristic histologic features and chromosomal alterations. Although typically indolent, a small subset of cases has been reported to exhibit aggressive clinical behavior. We retrospectively identified 33 patients with MTSCC, consisting of 10 cases of locally advanced/metastatic MTSCC (pT3 or N1 or M1) and 23 kidney-confined MTSCC (pT1/T2) without disease recurrence or progression. Utilizing a single-nucleotide polymorphism array and a targeted next-generation sequencing platform, we examined genome-wide molecular alterations in 24 cases, including 11 available samples from 8 patients with locally advanced/metastatic MTSCC. Ten patients with locally advanced/metastatic MTSCC were 8 females (80%) and 2 males (20%). At nephrectomy, 7 of these 10 cases (70%) were pT3 or pN1 while the remaining 3 (30%) were pT1/T2. Eight patients (80%) developed metastases and common sites included lymph node (4, 40%), bone (4, 40%), and retroperitoneum (3, 30%). Four patients died of disease (40%) during follow-up. Locally advanced/metastatic MTSCCs shared typical MTSCC genomic profiles with loss of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22, while some exhibited additional complex genomic alterations, most frequently a relative gain of 1q (7/8). Homozygous loss of CDKN2A/B was observed in 3 (38%) locally advanced/metastatic MTSCCs. Tumor necrosis, solid nested/sheet pattern, irregular trabecular/single-file infiltration in a desmoplastic stroma, lymphovascular space invasion, and increased mitotic activity were associated with locally advanced/metastatic MTSCCs (all p < 0.05). Our findings reveal that MTSCCs with aggressive clinical behavior have progressed through clonal evolution; CDKN2A/B deletion and additional complex genomic abnormalities may contribute to this process. Recognizing the morphologic presentation of high-grade MTSCC and evaluating adverse histologic features seen in these tumors can help establish a definitive diagnosis and stratify patients for treatment and prognostication.

Dataset Information

Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

Publications

Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

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