KRAS Mutations in Mucinous Lesions of the Uterus

He, Mai; Jackson, Cynthia L.; Gubrod, Rebecca Buell; Breese, Virginia; Steinhoff, Margaret M.; Lawrence, W. Dwayne; Xiong, Jinjun

doi:10.1309/ajcp69rbnuhhojri

Cited by 22 publications

(25 citation statements)

References 12 publications

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“…Many studies correlated KRAS status with certain histopathological features; Xiong et al supported the role of KRAS mutations in the formation of superficial epithelial changes in endometrioid EC, which has been further associated with focal mucinous differentiation (37). A similar association between KRAS and mucinous differentiation was reported by He et al (38). Another interesting study by Steward et al identified KRAS mutations in 12 out of 42 endometriosis-associated endometrioid adenocarcinomas (39).…”

Section: Translation Of Kras Mutation Status Into Clinical Informatiosupporting

confidence: 77%

The Role of KRAS in Endometrial Cancer: A Mini-Review

et al. 2019

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Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogenactivated protein kinase (MAPK) or phosphoinositide-3-kinase/vakt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as upregulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options. Endometrial cancer (EC) is the most common cancer of the female genital tract in developed countries (1). Each year 319,500 women are diagnosed with EC resulting in 76,000 deaths worldwide (2). EC develops from the inner lining of the uterine corpus (3), and it is currently divided into two types as firstly described by Llobet et al. (4). Type I tumours tend to be low or intermediate tumour grade; they overlap considerably (80%) with oestrogen-related endometrioid carcinomas. Contrary to type I, type II EC results from a sequence of genetic alterations occurring in atrophic endometrium; this can occasionally reflect a progression from polyps or pre-cancerous lesions to EC. Type II EC is mostly considered as non-endometrioid serous carcinomas (4); it tends to be high grade, deeply invasive into the myometrium, and of more advanced stage at presentation (4, 5). The estimated 5-year overall survival for patients with any type of EC is 81.5% (any stage) (6). Current Staging EC staging consensus keeps with the 2009 International Federation of Gynaecology and Obstetrics (FIGO) revised classification. Revised FIGO staging defines four stages 533 This article is freely accessible online.

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Section: Translation Of Kras Mutation Status Into Clinical Informatiosupporting

confidence: 77%

The Role of KRAS in Endometrial Cancer: A Mini-Review

et al. 2019

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“…In colorectal cancers, a KRAS mutation was detected in 35.6% of cases and is regarded as a useful predictive factor for the efficacy of anti‐epidermal growth factor receptor therapy (Van Cutsem et al, ). Furthermore, KRAS mutations were detected in various cancers at different frequencies, including thyroid gland cancer (Fukahori et al, ), biliary tract cancer (Kubicka et al, ), pulmonary adenocarcinoma (The Cancer Genome Atlas Research Network, ), testicular germ cell tumor (Litchfield et al, ), endometrial cancer (endometrioid carcinoma; Lax, Kendall, Tashiro, Slebos, & Hedrick, ; Zaino et al, ), mucinous adenocarcinoma (Alomari, Abi‐Raad, Buza, & Hui, ; He et al, ; Mackenzie et al, ; Yoo et al, ; Zaino et al, ), clear cell carcinoma (An, Logani, Isacson, & Ellenson, ; Zaino et al, ), ovarian cancer (low‐grade serous carcinoma), and serous borderline tumor (Boyd et al, ; Hunter et al, ; Jones et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, KRAS mutations were detected in various cancers at different frequencies, including thyroid gland cancer (Fukahori et al, 2012), biliary tract cancer (Kubicka et al, 2001), pulmonary adenocarcinoma (The Cancer Genome Atlas Research Network, 2014), testicular germ cell tumor (Litchfield et al, 2015), endome- (Alomari, Abi-Raad, Buza, & Hui, 2014;He et al, 2015;Mackenzie et al, 2015;Yoo et al, 2012;Zaino et al, 2014), clear cell carcinoma (An, Logani, Isacson, & Ellenson, 2004;Zaino et al, 2014), ovarian cancer (low-grade serous carcinoma), and serous borderline tumor (Boyd et al, 2013;Hunter et al, 2015;Jones et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors

et al. 2018

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Objective This study aimed to assess the frequency of KRAS mutation and its association with the presence of the MAPK/ERK signaling pathway proteins in adenomatoid odontogenic tumors. Study Design Paraffin‐embedded tissue samples from nine cases of adenomatoid odontogenic tumor were used. Genomic DNA was extracted from each sample; in one case, genetic mutations in 50 cancer‐associated genes were examined by next‐generation sequencing. Hotspot mutations in the RAS family were analyzed by Luminex assay using the remaining eight cases. Subsequently, immunohistochemistry for KRAS, CRAF, BRAF, EGFR, ERK, MEK, and BRAFV600E was performed. Results A KRAS G12D missense mutation was detected in the DNA sequence of the tumor cells, but it was not detected in the stromal tissue. KRAS G12V and KRAS G12R mutations were detected in two and four cases, respectively. For immunohistochemistry, all the cases were EGFR, KRAS, BRAF, CRAF positive, one case was ERK negative,and one case was MEK and ERK negative, all the other remaining cases were MEK and ERK positive. Conclusion KRAS mutation at codon 12 and the presence of MAPK/ERK pathway proteins were detected suggesting their association with tumorigenesis of adenomatoid odontogenic tumors.

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“…Mucinous, serous, clear cell, neuroendocrine, undifferentiated, and dedifferentiated carcinomas are classified as nonendometrioid ECs. 7,8 Among these, the refined definition of mucinous carcinoma is now specified as ECs with more than 50% of tumor cells containing intracytoplasmic mucin (Figure 2). 7,8 A subset of mucinous carcinomas, designated microglandular-like carcinoma due to its morphologic similarity to microglandular hyperplasia of the endocervical glands, is acknowledged by the WHO 2014 ( Figure 3).…”

Section: Advancements In Classification Ofmentioning

confidence: 99%

“…7,8 Among these, the refined definition of mucinous carcinoma is now specified as ECs with more than 50% of tumor cells containing intracytoplasmic mucin (Figure 2). 7,8 A subset of mucinous carcinomas, designated microglandular-like carcinoma due to its morphologic similarity to microglandular hyperplasia of the endocervical glands, is acknowledged by the WHO 2014 ( Figure 3). 9 Neuroendocrine tumors are now classified as low-grade neuroendocrine tumors (corresponding to carcinoids in previous classifications) and high-grade neuroendocrine carcinomas, encompassing small and large cell neuroendocrine carcinomas.…”

Section: Advancements In Classification Ofmentioning

confidence: 99%

Recent Developments in Surgical Pathology of the Uterine Corpus

Hanley

Birdsong

Mošunjac

2017

Archives of Pathology &Amp; Laboratory Medicine

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There have been several updates recently on the classification of uterine tumors. Endometrial carcinomas have traditionally been divided into 2 types, but some are difficult to classify and do not fit readily into either of the currently recognized categories. The Cancer Genome Atlas Research Network has recently defined 4 new categories of endometrial cancer on the basis of mutational spectra, copy number alteration, and microsatellite instability, which might provide independent prognostic information beyond established risk factors. The Society of Gynecologic Oncology, moreover, now recommends systematic screening of every patient with endometrial cancer for Lynch syndrome. The new definition of high-grade endometrial stromal sarcoma disregards the number of mitotic figures as a primary diagnostic criterion and instead specifies moderate atypia still resembling stromal origin but lacking the pleomorphism of undifferentiated uterine sarcoma; these tumors also harbor a JAZF1-SUZ12 gene rearrangement. Mitotic count, atypia, and coagulative necrosis are the main histologic criteria that define leiomyosarcoma. Determining the type of necrosis can be very challenging in patients receiving various treatment modalities for symptomatic fibroids before myomectomy, since key histologic features of ischemic-type necrosis are often absent. Ancillary stains including p16, p53, MIB-1, trichrome, and reticulin may be helpful in tumors harboring necrosis that is difficult to classify. Minimally invasive gynecologic surgeries have introduced histologic artifacts that complicate the diagnosis. It is essential to recognize these as procedure-related artifacts to avoid upstaging tumors and triggering unnecessary adjuvant treatment.

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KRAS Mutations in Mucinous Lesions of the Uterus

Abstract: The results suggest a possible association between KRAS mutations and mucinous differentiation in endometrial carcinogenesis. KRAS status can help in assessing benign from precursor or malignant mucinous lesions as well as differentiate endometrial lesions from those of cervical origin.

Cited by 22 publications

References 12 publications

The Role of KRAS in Endometrial Cancer: A Mini-Review

The Role of KRAS in Endometrial Cancer: A Mini-Review

Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors

Recent Developments in Surgical Pathology of the Uterine Corpus

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