Intratumoral heterogeneity in colorectal cancer: Can histology be used as a guidance for molecular testing?

Abstract

611 Background: Intratumour heterogeneity is a key challenge in colorectal cancer management. We have recently shown high levels of morphologic heterogeneity in microsatellite unstable (MSI) colorectal tumours (CRC). In this study we verified whether morphologic intratumour heterogeneity can be used as a guidance to test for molecular heterogeneity. Methods: 15 MSI CRCs tumour, characterized by a heterogenous morphology, were selected together with the associated metastasis. Macrodissection of the distinct morphologic tumour components was followed by MSI testing according to the Bethesda guidelines and Sanger sequencing for BRAF V600E mutations. In addition, 2 MSI CRC underwent macrodissection of the distinct morphologic components, followed by nanostring ncounter analysis. Results: MSI status varies between MSI-H and MSI-L in the primary tumours and 35% of the metastasis of MSI-H primary tumours presented as MSI-L or MSS. BRAF mutations status was constant throughout the primary tumours, but two BRAF mutated tumours presented with a BRAF wild type metastasis. Nanostring analysis revealed that ùorphologically identical clones clustered separately from tumour clones with a different morphologic display. Conclusions: Morphologically heterogeneous tumour compartments have less related gene expression profiles, linking morphologic homogeneity to molecular homogeneity. Our findings support the hypothesis that morphologic heterogeneity reflects molecular intratumour heterogeneity and can be used as a guidance for molecular testing of colorectal cancers.

Conversion of Unresectable to Resectable Liver Metastases from Colorectal Carcinoma Using Hepatic Arterial Chronomodulated Chemotherapy: A Case Report and Short Literature Review

“…Despite the inefficiency of nivolumab in this case, initial analysis of nivolumab plus ipilimumab in patients with ≥6 months follow-up demonstrated a manageable safety profile and clinical activity characterized by a 55% overall response rate and 80% disease control rate in patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC [21]. The ineffectiveness of nivolumab in this case may be due to the extensive heterogeneity in microsatellite unstable (MSI) between primary tumor and metastases, which has been recently shown in colorectal tumours [22]. Soimmunotherapy role even in patients with MSI status is not a landmark of response to anti-PD1 agents.…”

Microsatellite instability as a unique characteristic of tumors and a predictor of response to immune therapy

“…Внутриопухолевая гетерогенность встречается не чаще 5 % [60], тогда как несоответствие статуса между первичной опухолью и метастазами изучено недостаточно. В одной из работ у всех 137 пациентов с КРР статус MSI в первичной опухоли и метастазах совпадал [61], в другом исследовании несоответствие составило 35 % [62]. Столь высокая частота несоответствия может быть объяснена методологическими особенностями: гетерогенность оценивалась не между MSI и MSS (как принято в настоящее время), а между MSI-high, MSI-low и MSS.…”

A multi-modal data resource for investigating topographic heterogeneity in patient-derived xenograft tumors

“…CRCs exhibit well-characterized primary tumor location (left vs. right colon) and molecular subtype 16 heterogeneity. Certain histological variants of CRC show a higher degree of tumor heterogeneity than others, with microsatellite unstable (MSI) CRC in particular showing high levels of morphologic heterogeneity 17 . For our study, we selected four models of mCRC, two originating from the right colon (PDX-R1, PDX-R2) and two originating from the left (PDX-L1, PDX-L2) colon (see Table 1 for additional information on the PDX models).…”