Genotype-phenotype associations in colorectal adenocarcinomas and their matched metastases

Kyriakos Chatzopoulos; Vassiliki Kotoula; Georgia-Angeliki Koliou; Eleni Giannoulatou; Kyriaki Papadopoulou; Vasilios Karavasilis; Elissavet Pazarli; Stavroula Pervana; Georgia Kafiri; Georgios Tsoulfas; Sofia Chrisafi; Helen Sgouramali; Pavlos Papakostas; Dimitrios Pectasides; Prodromos Hytiroglou; George Pentheroudakis; George Fountzilas

doi:10.1016/j.humpath.2020.10.009

Genotype-phenotype associations in colorectal adenocarcinomas and their matched metastases

Hum Pathol. 2021 Jan:107:104-116. doi: 10.1016/j.humpath.2020.10.009. Epub 2020 Nov 5.

Authors

Kyriakos Chatzopoulos¹, Vassiliki Kotoula², Georgia-Angeliki Koliou³, Eleni Giannoulatou⁴, Kyriaki Papadopoulou⁵, Vasilios Karavasilis⁶, Elissavet Pazarli⁷, Stavroula Pervana⁷, Georgia Kafiri⁸, Georgios Tsoulfas⁹, Sofia Chrisafi⁵, Helen Sgouramali⁵, Pavlos Papakostas¹⁰, Dimitrios Pectasides¹⁰, Prodromos Hytiroglou¹¹, George Pentheroudakis¹², George Fountzilas¹³

Affiliations

¹ Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, 54124, Greece. Electronic address: Chatzopoulos.Kyriakos@mayo.edu.
² Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, 54124, Greece.
³ Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, 11524, Greece.
⁴ Computational Genomics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; The University of New South Wales, Kensington, NSW, 2052, Australia.
⁵ Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
⁶ Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, 56403, Greece.
⁷ Department of Pathology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, 56403, Greece.
⁸ Department of Pathology, Hippokration Hospital, Athens, 11527, Greece.
⁹ Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
¹⁰ Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, 11527, Greece.
¹¹ Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, 54124, Greece.
¹² Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, 45500, Greece; Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.
¹³ Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; Aristotle University of Thessaloniki, Thessaloniki, Greece; German Oncology Center, Limassol, Cyprus.

PMID: 33161028
DOI: 10.1016/j.humpath.2020.10.009

Abstract

Although primary colorectal carcinomas (CRCs) frequently share genetic alterations with their metastases, morphologic surrogates reflecting the genotype contexture of metastases remain largely unknown. We investigated phenotype/genotype associations in paired primary and metastatic colorectal adenocarcinomas from 75 patients. Thirty-three (44%) metastatic lesions were synchronous and 42 (56%) were metachronous. Tumor budding, micronecrosis, and tumor-infiltrating lymphocyte (TIL) density were compared with matched next-generation sequencing genotypes. Micronecrosis in the primary were significantly associated with nodal status (P = 0.0054) and with micronecrosis in metastatic sites (P = 0.0216), particularly in metachronous metastases (P = 0.0033). With a 57-gene panel, one or more mutations were identified in 64 (85.3%) cases. In metastases, high (brisk) TILs were associated with overall mutational burden (P = 0.0058) and with mutations in EGF (P = 0.0325), RAS genes (P = 0.0043), and MMR genes (P = 0.0069), whereas high-level micronecrosis correlated with mutations in APC (P = 0.0004) and MSH6 (P = 0.0385) genes. Genomic alterations were shared in 90.1% of primary/metastatic pairs, but clonality of the same mutation was shared in only 57.1% of paired lesions. Compared with synchronous, metachronous metastases had more private clonal alterations (P = 0.0291); in this group, clonal alterations coincided with brisk TILs (P = 0.0334) and high micronecrosis (P = 0.0133). High TILs in metastatic lesions were predictive of favorable overall survival (log-rank P = 0.044). The observed phenotype/genotype associations favor the clonal evolution model in CRC metastases that seems accompanied by intense host immune response. If the role of micronecrosis and brisk TILs in metachronous metastases is validated in larger studies, these histologic parameters will be worth adding in the armamentarium for the evaluation of metastatic CRC.

Keywords: Clonal evolution; Colorectal neoplasms; Lymphocytes; Necrosis; Neoplasm metastasis; Next-generation sequencing; Tumor-infiltrating.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / immunology
Adenocarcinoma / pathology*
Adult
Aged
Aged, 80 and over
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / immunology
Colorectal Neoplasms / secondary*
Female
Genetic Association Studies
Humans
Lymphocytes, Tumor-Infiltrating / immunology
Male
Middle Aged
Neoplasm Metastasis / genetics*
Neoplasm Metastasis / immunology
Neoplasm Metastasis / pathology