Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations.
نویسندگان
چکیده
PURPOSE We queried whether comprehensive genomic profiling using a next-generation sequencing-based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC). EXPERIMENTAL DESIGN DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC. RESULTS A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1-6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0-3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P = 0.0006). CONCLUSIONS Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC.
منابع مشابه
Relapsed classic E-cadherin (CDH1) mutated invasive lobular breast cancer demonstrates a high frequency of HER2 (ERBB2) gene mutations
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Hypermethylation of E-Cadherin and Estro-gen Receptor- Gene Promoter and Its Association with Clinicopathological Features of Breast Cancer in Iranian Patients
Background: Aberrant methylation of cytosine-guanine dinucleotide islands leads to inactivation of tumor suppressor genes in breast cancer. Tumor suppressor genes are unmethylated in normal tissue and often become hypermethylated during tumor formation, leading to gene silencing. We investigated the association between E-cadherin (CDH1) and estrogen receptor-α (ESRα) gene promoter methylation a...
متن کاملERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast
E-cadherin (CDH1) is a glycoprotein that mediates adhesion between epithelial cells and also suppresses cancer invasion. Mutation or deletion of the CDH1 gene has been reported in 30-60% cases of invasive lobular carcinoma (ILC). However, little is known about genomic differences between ILC with and without a CDH1 alteration. Therefore, we analyzed whole genome sequencing data of 169 ILC cases...
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Genome sequencing of relapsed, invasive lobular breast cancer identified actionable mutations in 86% of the cases. HER2 alterations occur in 27% of the cases, including 4 cases with activating HER2 mutations and 1 with a novel HER2-GRB7 gene fusion. This fusion links the HER2 tyrosine kinase domain to the GRB7 src homology 2 (SH2) domain.
متن کاملGermline E-cadherin mutations in familial lobular breast cancer.
BACKGROUND The cell surface glycoprotein E-cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well established as the defects underlying hereditary diffuse gastric cancer (HDGC) syndrome, and an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in ...
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عنوان ژورنال:
- Clinical cancer research : an official journal of the American Association for Cancer Research
دوره 19 10 شماره
صفحات -
تاریخ انتشار 2013