Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer

Abstract

BackgroundClinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics.MethodsThere were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher’s exact test compared each pair of genes. A similarity score was constructed with the resulting P-values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients.ResultsGene-by-gene analysis found that CCND1 mutations were positively correlated with ER status while ERBB2 and CDK12 mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 (ADGRA2, ZNF703, FGFR1, KAT6A, and POLB) was significantly associated with PR status; gene cluster 2 (COL1A1, AXIN2, ZNF217, GNAS, and BRIP1) and gene cluster 3 (FGF3, FGF4, FGF19, and CCND1) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively.ConclusionThis study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance.

ERBB2‐amplified lobular breast carcinoma exhibits concomitant CDK12 co‐amplification associated with poor prognostic features

“…Molecular alterations in most lobular breast carcinomas involve somatic genetic alterations in the CDH1 gene locus on 16q22.1 resulting in loss of function of the CDH1 gene, loss of IHC staining for E‐cadherin protein, and typical dyscohesive spread of invasive lobular carcinoma cells [ 1 , 7 , 22 ]. This molecular phenomenon together with further alterations of the catenin adherens complex (such as alfa‐catenin, beta‐catenin, and catenin p120) has become a useful diagnostic tool in the histopathological diagnosis of invasive lobular carcinoma [ 1 , 7 , 22 ]. This phenomenon was also observed in some precursor HER2‐positive LCIS lesions, possible pointing to stepwise evolution of HER2‐positive ILC along with CDK12 amplification.…”

“…This phenomenon was also observed in some precursor HER2‐positive LCIS lesions, possible pointing to stepwise evolution of HER2‐positive ILC along with CDK12 amplification. Membranous loss of the E‐Cadherin and the catenin complex detected by IHC with corresponding dissolute cellular morphology helps to distinguish lobular breast carcinoma from NST carcinoma and supports the diagnosis of lobular differentiation in about 85% of ILBC [ 1 , 7 , 22 ]. In line with the current WHO guidelines, the histological diagnosis of invasive lobular carcinoma is based on H&E morphology and on the immunohistochemical characterization of E‐cadherin and the catenin complex independently from the presence of underlying CDH1 gene mutations [ 1 , 7 , 22 ].…”

“…Membranous loss of the E‐Cadherin and the catenin complex detected by IHC with corresponding dissolute cellular morphology helps to distinguish lobular breast carcinoma from NST carcinoma and supports the diagnosis of lobular differentiation in about 85% of ILBC [ 1 , 7 , 22 ]. In line with the current WHO guidelines, the histological diagnosis of invasive lobular carcinoma is based on H&E morphology and on the immunohistochemical characterization of E‐cadherin and the catenin complex independently from the presence of underlying CDH1 gene mutations [ 1 , 7 , 22 ]. CDH1 gene mutation, even though frequent in ILBC, does not, according to current guidelines, per se define or exclude lobular differentiation alone and molecular CDH1 status should be interpreted only together with the morphology [ 1 , 7 , 22 ].…”

“…In line with the current WHO guidelines, the histological diagnosis of invasive lobular carcinoma is based on H&E morphology and on the immunohistochemical characterization of E‐cadherin and the catenin complex independently from the presence of underlying CDH1 gene mutations [ 1 , 7 , 22 ]. CDH1 gene mutation, even though frequent in ILBC, does not, according to current guidelines, per se define or exclude lobular differentiation alone and molecular CDH1 status should be interpreted only together with the morphology [ 1 , 7 , 22 ].…”

Tumor grade-associated genomic mutations in Chinese patients with non-small cell lung cancer

“…The library construction and sequencing were performed in the CLIA/CAP-compliant Molecular Diagnostics Service laboratory of Shanghai Origimed Co., Ltd. The detailed procedure had been described in our previous works (7)(8)(9). Briefly, typically 50-250 ng of double-stranded DNA was fragmented to ~250 bp by sonication.…”