Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and <i>TP53</i>-Mutant Tumors and Identifies <i>NRAS</i> as an Oncogenic Driver

We aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

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“…Participating studies 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 …”

Section: Supporting Informationmentioning

confidence: 99%

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Rambau

Vierkant

Intermaggio

et al. 2018

The Journal of Pathology CR

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“…KRAS mutation is 0% to 5% in non-endometrioid endometrial cancers. [46][47][48][49][50][51][52][53][54][55][56] The frequency of KRAS mutations in cervical cancer ranges between 5% and 14%. In the United States, the frequency of KRAS mutation is 8.8% in patients with cervical cancer.…”

Section: Frequency Of Ras Mutation In Genitourinary Cancermentioning

confidence: 99%

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Kodaz

2017

EJMO

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T he RAS oncogene affects numerous cellular functions, including growth, proliferation, apoptosis, migration, division, and differentiation of the cells. It has 3 known isoforms: Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity; it encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies conducted on cancer-causing viruses. Retroviral oncogenes related to murine sarcoma virus genes (Kristen rat sarcoma virus and Harvey rat sarcoma virus) were discovered in 1982. These 2 oncogenes are similar to human KRAS. Approximately 30% of all human cancers have RAS gene involvement. Mutations in KRAS account for about 85% of all RAS mutations in human tumors, NRAS for about 11% to 15%, and HRAS for about 1%. Frequency of RAS mutation in intracranial tumorsGliomas constitute 80% of malignant brain tumors. RAS mutations are very rare in malignant gliomas; no RAS mutation was found in a study in which 30 glioblastoma multiforme (GBM) patients were evaluated. The frequency of NRAS mutation was 2.1% in another study, although KRAS and HRAS mutations were not detected. It was reported that RAS mutation frequency was 12% in a study of isocitrate-dehydrogenase 1-mutant malignant glioma. RAS genes were studied in 21 cases of glioblastoma multiforme, 4 cases of fibrillary astrocytoma, 4 cases of anaplastic astrocytoma, and 15 normal specimens. RAS mutation was de-RAS oncogene affects numerous cellular functions including growth, proliferation, apoptosis, migration, division and differentiation of the cells. It has 3 known isoforms as Harvey-RAS (HRAS), Kirsten -RAS (KRAS) and Neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity. It encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies carried out on viruses leading to cancer. Retroviral oncogenes related to murine sarcoma virus genes (Kristen Rat Sarcoma Virus and Murine Sarcoma Virus) were discovered in 1982. These two oncogenes are similar to human KRAS. Approximately 30% of all human cancers have ras genes. Mutations in KRAS account for about 85% for all RAS mutations in human tumors, NRAS is about 11-15%, and HRAS is about 1%.

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“…Prior analyses have been inadequately powered to evaluate histotype-specific survival associations. This is critical, as the invasive histotypes (high-grade serous, HGSOC, the most common and most lethal; 13 endometrioid, ENOC; 14 clear cell, CCOC; 14,15 mucinous, MOC; 16 and low-grade serous, LGSOC 17–20 ) represent distinct biological processes, with distinct proposed cells of origin, clinical courses, and responses to chemotherapy. 21–23 …”

Section: Introductionmentioning

confidence: 99%

Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Goode¹,

Block²,

Kalli³

et al. 2017

JAMA Oncol

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278

181

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Importance Cytotoxic CD8+ T lymphocytes (TILs) participate in immune control of ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design Prospective survival cohort. Setting Multi-center observational. Participants Over 5,500 patients, including 3,196 high-grade serous ovarian carcinomas (HGSOCs), followed prospectively for over 24,650 person-years. Exposure(s) Following immunohistochemistry, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1–2), moderate (3–19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcome Measure(s) Overall survival time. Results Among the five major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (p-trend=4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors which drive infiltration will be key to unravelling outcome heterogeneity in this cancer.

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Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

Cited by 97 publications

References 49 publications

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

Cited by 97 publications

References 49 publications

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer