An amino-terminal BRAF deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer.

Although combination therapy with RAF and EGFR inhibitors has improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating mutations in RASgenes, MAP2K mutations, and amplifications in BRAF, RAS genes, and EGFR In this report, we describe a patient with BRAF-mutated CRC who acquired an amino-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. Amino-terminal BRAF deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC for which there is only one prior report in the literature.

Identification of aggressive Gardner syndrome phenotype associated with a de novo APC variant, c.4666dup.

Gardner syndrome describes a variant phenotype of familial adenomatous polyposis (FAP), primarily characterized by extracolonic lesions including osteomas, dental abnormalities, epidermal cysts, and soft tissue tumors. We describe a 2-yr-old boy presenting with a 2-cm soft tissue mass of the forehead. Pathologic evaluation revealed a nuchal-type/Gardner-associated fibroma. Sequencing of the APC gene revealed a pathologic variant c.4666dupA. Parental sequencing of both blood and buccal tissue supported the de novo occurrence of this pathologic variant. Further imaging revealed a number of additional lesions including a large lumbar paraspinal desmoid, a 1-cm palpable lesion posterior to the left knee, firm lesions on bilateral heels, and multiple subdermal lesions. Colonoscopy was negative. This case illustrates a genetic variant of Gardner syndrome resulting in an aggressive early childhood phenotype and highlights the need for an individualized approach to treatment.

Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases.

ERBB2 amplification has been identified in ∼5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2-amplified CRC. PCR-free whole-genome sequencing was used to identify mutations, copy-number alterations, structural variations, and losses of heterozygosity. ERBB2 copy number was also measured by fluorescence in situ hybridization. Single-stranded mRNA sequencing was used for gene expression profiling. Immunohistochemistry and protein mass spectrometry were used to quantify HER2 protein expression. The cases showed ERBB2 copy number of 86 and 92, respectively. Both cases were immunohistochemically positive for HER2 according to CRC-specific scoring criteria. Fluorescence in situ hybridization and protein mass spectrometry corroborated significantly elevated ERBB2 copy number and abundance of HER2 protein. Both cases were microsatellite stable and without mutation of RAS pathway genes. Additional findings included altered expression of PTEN, MET, and MUC1 and mutation of PIK3CA The potential effects of the molecular alterations on sensitivity to EGFR and HER2-directed therapies were discussed. Identification of ERBB2 amplification in CRC is necessary to select patients who may respond to HER2-directed therapy. An improved understanding of the molecular characteristics of ERBB2-amplified CRCs and their potential mechanisms of resistance will be useful for future research into targeted therapies and may eventually inform therapeutic decision-making.