Rare genetic heterogeneity within single tumor discovered for the first time in colorectal liver metastases after liver resection
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Mylène Sebagh1,2,3,4, Nelly Bosselut2,3,4,5, Alexandre Dos Santos2,3,4, Marc-Antoine Allard2,3,4,6,7, Aldrick Ruiz6,8, Raphaël Saffroy2,3,4,5, Daniel Cherqui2,3,4,6, Eric Vibert2,3,4,6, Denis Castaing2,3,4,6, René Adam3,4,6,7, Antonio Sa Cunha2,3,4,6 and Antoinette Lemoine2,3,4,5
1AP-HP Hôpital Paul Brousse, Laboratoire d’Anatomie Pathologique, Villejuif, France
2Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
3Univ Paris-Sud, UMR-S 1193, Université Paris-Saclay, Villejuif, France
4DHU Hepatinov, Villejuif, France
5AP-HP Hôpital Paul Brousse, Département d’Oncogénétique, Villejuif, France
6AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France
7Inserm, Unité 935, Université Paris-Saclay, Villejuif, France
8University Medical Center Utrecht, Department of Surgery, Utrecht, The Netherlands
Mylène Sebagh, email: [email protected]
Keywords: colorectal liver metastases; intratumoral genetic heterogeneity; pathological response; mutations
Received: June 05, 2017 Accepted: March 21, 2018 Published: April 24, 2018
Effective individualized treatment of patients with colorectal liver metastases (CLM) requires tumor genotyping, usually based on the analysis of one single sample per patient. Therapy failure may partially be explained by sampling errors and/or intratumoral genetic heterogeneity. We aimed to demonstrate intratumoral genetic heterogeneity in CLM and enable pathologists to select tumor tissue for genotyping. All the tumors of 86 patients who underwent liver resection for a single CLM were reviewed. Of the 86 patients, 66 patients received chemotherapy and 20 patients did not receive chemotherapy before liver resection. All the tumor areas sampled were analyzed for KRAS, BRAF, PIK3CA, and NRAS mutations. The mutational status was tested in 74 cases, 7 cases had no tumoral cells due to complete responses and 5 blocks were unavailable. Of the 59/74 CLM with > 1 sample, 56 showed the same mutational status between the samples. The remaining 3 cases (5% of all cases) showed genetic heterogeneity for KRAS in 2 and BRAF in 1 patient. Genetic heterogeneity correlated with lower rate of viable tumor cells (p=0.009) and higher rate of mucin pools (p=0.013). We demonstrate for the first time the existence of genetic intratumoral heterogeneity in 5% of CLM. In routine practice, this low incidence does not require the genotyping of additional tumor samples. The correlation between the genetic heterogeneity and some histological components of the CLM should be verified by further in situ mutation assay.
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