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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish
Pages (from-to)104-116
Number of pages13
JournalHuman Pathology
StatePublished - Jan 2021
Externally publishedYes


  • Clonal evolution
  • Colorectal neoplasms
  • Lymphocytes
  • Necrosis
  • Neoplasm metastasis
  • Next-generation sequencing
  • Tumor-infiltrating


Dive into the research topics of 'Genotype-phenotype associations in colorectal adenocarcinomas and their matched metastases'. Together they form a unique fingerprint.

Cite this