FGFR2 amplification in colorectal adenocarcinoma

Abstract

FGFR2 is recurrently amplified in 5% of gastric cancers and 1%-4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.

Keywords: colon cancer; neoplasm of the gastrointestinal tract.

Figure 1.

Neuroendocrine marker immunostains. (Top) H&E, 2×. Poorly differentiated, signet-ring adenocarcinoma showing abundant mucin in this section. (Bottom left) Synaptophysin, 20×. Focal expression present in the malignant cells. (Bottom right) Chromogranin, 20×. Malignant glands showing patchy expression.

Figure 2.

MMR immunostains showing retained expression of all four MMR markers. (Top left) MLH1, 20×. (Top right) MSH2, 20×. (Bottom left) MSH6, 20×. (Bottom right) PMS2, 20×.

Figure 3.

Multimodal analysis of FGFR2 in the tumor. (A) Targeted NGS-based virtual karyotype (CNVkit) showing background aneuploidy and an amplification event involving a focal region of Chromosome 10 (Chr10:122737302–123454446) that includes FGFR2. (B) Cytoscan microarray output from the tumor tissue revealing amplification of the region involving FGFR2. (C) Fluorescence in situ hybridization of tumor-involved (Tumor) and tumor-uninvolved (Control) colonic tissue from the patient's colectomy. FGFR2 probe (RP11–62L18, red) to Chromosome 10 enumeration probe (CEP 10, green) ratio showing a high copy-number ratio of 24.2 in the tumor (right) versus 1.92 in the control (left).