Coexistence of two different mutations in codon 12 of the Kras gene in colorectal cancer: Report of a case supporting the concept of tumoral heterogeneity

Improta, Giuseppina; Zupa, Angela; Possidente, Luciana; Tartarone, Alfredo; Pedicini, P.; Nappi, Antonio; Molinari, S.; Fraggetta, Filippo; Vita, Giulia

doi:10.3892/ol.2013.1255

Cited by 12 publications

(12 citation statements)

References 27 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We identified the coexistence of different KRAS mutations as well as KRAS and NRAS mutations. Coexistence of different KRAS 12−13 mutations has been reported by others on small series [24,25,26]. To our knowledge, the present study is one of the first reports concerning the coexistence of mutations in codons 12–13, 61 and 146 of KRAS (17% of cases).…”

Section: Discussionsupporting

confidence: 77%

“…Several neoplastic subclones with co-existing mutations in different genes (as well as different molecular alterations) could be present in a single primary tumor with different mutant allele frequencies [19,20,23,24,25]. In our study, by testing KRAS and NRAS mutations in histologically relevant macrodissected zones according to pTNM, we observed the presence of (i) mutational intra-tumor heterogeneity with at least two co-existing KRAS and/or NRAS mutations within the same tumor areas and (ii) spatial intra-tumoral heterogeneity with coexistence within the same tumor of KRAS and/or NRAS mutated zones and WT zones.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

Jeantet

Tougeron

Tachon

et al. 2016

IJMS

View full text Add to dashboard Cite

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM) staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity for RAS mutation was found in 33% of cases. Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multiple RAS mutated subclones in the same tumor. A high proportion of CRCs presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

Jeantet

Tougeron

Tachon

et al. 2016

IJMS

View full text Add to dashboard Cite

show abstract

“…We detected double, triple, and even quadruple mostly subclonal somatic mutations affecting these genes in almost half of the cases. While multiple KRAS mutations in CRC have been reported in individual cases (Macedo et al, ; Improta et al, ), to our knowledge such patterns have not been described for PIK3CA and TGFBR2 in CRC before. Our data indicate that in some cases both alleles may be affected while other mutations appear to occur at quite variable allelic frequencies suggesting competing subclones (Table ) that drive and foster tumor evolution (Burrell et al, ).…”

Section: Discussionmentioning

confidence: 60%

Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies

Jesinghaus

Pfarr

Kloor

et al. 2015

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Synchronous colorectal carcinomas (sCRC) are clinically challenging neoplasms. Although the epidemiological characteristics are quite well established, their biological basis is still poorly understood. Hence, we performed comprehensive molecular profiling of 23 sCRC cases comprising 50 synchronous primary tumors, 5 metastases, and corresponding normal tissue by targeted deep sequencing of 30 CRC-related genes, microsatellite analysis and analysis for methylated MLH1. We identified a striking inter- and intratumoral genetic heterogeneity of sCRC. Twenty (87%) cases showed genetic heterogeneity leaving only three cases with tumors that had an identical genetic make-up. Intertumoral heterogeneity was frequently observed for clinically actionable genes, including KRAS. Specifically, 44% of the cases harbored tumors of which at least one was KRAS mutated and the other KRAS wildtype. Moreover, 48% of the cases had at least double, sometimes even triple or quadruple mutations in KRAS, APC, TP53, PIK3CA, and TGFBR2, most of them being subclonal events. Lastly, we detected four cases (17%) with microsatellite instable (MSI) tumors with one case harboring one MSI- and a distinct microsatellite stable carcinoma. Our data demonstrate a striking genetic heterogeneity not only between different sCRC of a single case but also within a single tumor. These results contribute to the biological understanding of sCRC and directly impact genotyping strategies and oncological decision making. Testing one tumor or a single metastasis may not suffice in the sCRC setting as clinically relevant and tumor-specific genetic information may be left undetected compromising optimal oncological therapy. © 2015 Wiley Periodicals, Inc.

show abstract

“…They also detected tumours harbouring two concomitant KRAS mutations. Other authors have subsequently confirmed these same findings [26][27][28]31]. Based on these studies, it is recommended that tests for RAS status be conducted on metastatic tissue.…”

Section: Laboratory Accreditationmentioning

confidence: 52%

Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

et al. 2014

View full text Add to dashboard Cite

Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely.

show abstract

Coexistence of two different mutations in codon 12 of the Kras gene in colorectal cancer: Report of a case supporting the concept of tumoral heterogeneity

Cited by 12 publications

References 27 publications

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies

Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Contact Info

Product

Resources

About