Intratumoural heterogeneity may hinder precision medicine strategies in patients with clear cell renal cell carcinoma

Raspollini, Maria Rosaria; Montagnani, Ilaria; Montironi, Rodolfo; Castiglione, Francesca; Martignoni, Guido; Cheng, Liang; López-Beltrán, Antonio

doi:10.1136/jclinpath-2017-204931

Cited by 7 publications

(7 citation statements)

References 18 publications

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“…Maybe it is because PIK3CA mutations are rare in ccRCC and are present only in 2-5% of tumors [46] or result from intratumoral molecular heterogeneity which should be studied by novel sampling strategies [47]. Similarly to other authors [47][48][49][50] we also did not detect mutations in KRAS gene. It seems that mutations in PIK3CA and KRAS are not significant events in the development of ccRCC.…”

Section: Emt In Localized Ccrccsupporting

confidence: 65%

Biomarkers of epithelial-mesenchymal transition in localized, surgically treated clear-cell renal cell carcinoma

Gasińska

Jaszczyński

Adamczyk

et al. 2019

Folia Histochem Cytobiol.

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Introduction. It has been suggested that the metastatic potential of neoplastic cells can be predicted on the basis of their biological features, including expression of proteins involved in the epithelial to mesenchymal transition (EMT). Therefore, the purpose of this work was to (1) evaluate the expression of EMT markers: ZEB2, vimentin, N-cadherin, TWIST, PTEN, survivin, E-cadherin, Ki-67 and GLUT-1, (2) assess mutation status of two genes: PIK3CA and KRAS, and (3) investigate the potential relationships between the studied biomarkers and clinicopathological factors in clear-cell renal cell carcinoma (ccRCC). Material and methods. Tumor tissue samples (embedded in paraffin blocks) from 159 patients undergoing radical nephrectomy were analyzed. Proteins expression was evaluated immunohistochemically. DNA mutations were analyzed on DNA isolated from tumor tissue and amplified by real-time PCR detection using suitable fluorescent labeled TaqMan assays. Results. One hundred and seven men and 52 women of mean age of 63.1years were enrolled. Fifty four cancers at pTNM stage I-II and 98 at pTNM III-IV stage were diagnosed. There were 30 Fuhrman grade G1, 61 Fuhrman G2, 49 Fuhrman G3 and 19 Fuhrman G4 tumors. A negative correlation between ZEB2 (p = 0.047, r = -0.172) or E-cadherin expression (p = 0.027, r = -0.191) and TNM was observed. Positive association between grade and Ki-67 (p < 0.001), survivin (p < 0.001), vimentin (p < 0.001) immunoreactivity and negative association between TWIST expression (p = 0.029) or PTEN expression (p = 0.013) were found. Ki-67 expression was positively correlated with survivin (p < 0.001, r = 0.617), vimentin (p = 0.001, r = 0.251) and N-cadherin (p = 0,009, r = 0.207) immunoreactivity which can suggest tumor aggressiveness. TWIST was negatively correlated with E-cadherin (p < 0.001, r = -0.284), vimentin (p < 0.001, r = -0.297) and N-cadherin (p < 0.002, r = -0.241). ZEB2 was not associated with ccRCC grade but was negatively correlated with E-cadherin (p = 0.055, r= -0.153) and PTEN (p = 0.006). GLUT-1 expression was inversely linked to E-cadherin expression (p = 0.022, r= -0.182). Mutations in PIK3CA and KRAS genes were not found in any of the studied ccRCC tumors. Conclusions. Low-grade tumors showed higher expression of ZEB2 and TWIST proteins than high-grade tumors, which can suggest that EMT in ccRCC begins at early stages of tumor development and, therefore, evaluation of these proteins, together with other biomarkers, may be useful for assessment of the tumor metastatic potential.

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Section: Emt In Localized Ccrccsupporting

confidence: 65%

Biomarkers of epithelial-mesenchymal transition in localized, surgically treated clear-cell renal cell carcinoma

Gasińska

Jaszczyński

Adamczyk

et al. 2019

Folia Histochem Cytobiol.

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“…However, for functional molecular biology, e.g., gene expression, results for samples containing 20 to 30% cancer cells may be misleading in terms of interpretation, and therefore for adequate therapeutic options. Indeed, several studies demonstrate the need to overcome issues related to tumor heterogeneity prior to developing precision oncology strategies by showing that multiple regions of the same tumor can present different morphological and genetic features [ 150 , 151 ]. Moreover, the relatively slow-cycling, low-frequency stem cell phenotype populations may be those most involved in recurrences [ 152 ].…”

Section: Conceptual Diagnostic and Therapeutic Implications Of The Dynamic Heterogeneity Of Cancermentioning

confidence: 99%

“…In addition, intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through “Darwinian evolution”. This point has been emphasized for thyroid [ 13 ], renal carcinoma [ 151 ], and mammary tumors [ 159 ]. Indeed, the progression-free survival of many cancers after specific drug treatment, e.g., of such treated small-cell lung cancers, are not impressive [ 160 , 161 ].…”

Section: Conceptual Diagnostic and Therapeutic Implications Of The Dynamic Heterogeneity Of Cancermentioning

confidence: 99%

Dynamic Cancer Cell Heterogeneity: Diagnostic and Therapeutic Implications

Jacquemin

Antoine

Dom

et al. 2022

Cancers

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Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities rather than as an independent heterogeneous cooperative cell population with its self-oriented biology. There are, therefore, conceptual gaps which can mislead the interpretations/diagnostic and therapeutic approaches. In this short review, we wish to summarize and discuss various aspects of this dynamic evolving heterogeneity and its biological, pathological, clinical, diagnostic, and therapeutic implications, using thyroid carcinoma as an illustrative example.

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“…In the era of precision medicine, there is a need for histology-specific biomarkers and targeted therapies [5]. This endeavor is complicated by the well-known intra-tumor heterogeneity of RCCs as even within the same histological subtype, several morphological patterns and features can be present [6] and different molecular alterations can be found [7,8].…”

Section: Introductionmentioning

confidence: 99%

The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth

et al. 2021

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Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic “type 1 versus type 2” classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth.

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Intratumoural heterogeneity may hinder precision medicine strategies in patients with clear cell renal cell carcinoma

Cited by 7 publications

References 18 publications

Biomarkers of epithelial-mesenchymal transition in localized, surgically treated clear-cell renal cell carcinoma

Biomarkers of epithelial-mesenchymal transition in localized, surgically treated clear-cell renal cell carcinoma

Dynamic Cancer Cell Heterogeneity: Diagnostic and Therapeutic Implications

The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth

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