Identification of second primary tumors from lung metastases in patients with esophageal squamous cell carcinoma using whole-exome sequencing

Abstract

Esophageal squamous cell carcinoma (ESCC) patients with a synchronous or metachronous lung tumor can be diagnosed with lung metastasis (LM) or a second primary tumor (SPT), but the accurate discrimination between LM and SPT remains a clinical dilemma. This study aimed to investigate the feasibility of using the whole-exome sequencing (WES) technique to distinguish SPT from LM. Methods: We performed WES on 40 tumors from 14 patients, including 12 patients with double squamous cell carcinomas (SCCs) of the esophagus and lung (lymph node metastases were sequenced as internal controls) diagnosed as LM according to pathological information and 2 patients with paired primary ESCC and non-lung metastases examined as external controls. Results: Shared genomic profiles between esophageal (T) and lung (D) tumors were observed in 7 patients, suggesting their clonal relatedness, thus indicating that the lung tumors of these patients should be LM. However, distinct genomic profiles between T and D tumors were observed in the other 5 patients, suggesting the possibility of SPTs that were likely formed through independent multifocal oncogenesis. Conclusions: Our data demonstrate the limitations and insufficiency of clinicopathological criteria and that WES could be useful in understanding the clonal relationships of multiple SCCs.

Integrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics

“…Since 2012, there had been dozens of investigations published using the whole-genome sequence (WGS) or whole-exome sequence (WES) strategy to explore the genetics of ESCC. These studies depicted the general mutational landscape of ESCC, including the significantly mutated genes such as TP53, CDKN2A, EP300, PIK3CA, and NOTCH1, the commonly influenced pathways such as PI3K-AKT axis, cell cycle, and histone modification, and the commonly identified agerelated and APOBEC enzymes-related mutational signatures [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] .…”

The Role of Whole Exome Sequencing in Distinguishing Primary and Secondary Lung Cancers

“… 65 Xue et al analysed WES from 12 patients found to have squamous cell carcinomas of the esophagus and lung. 66 Similar to WES from multiple lung cancers, the authors identified one set of tumor pairs with no overlapping mutations, consistent with distinct lung and esophageal primaries, whereas a second group shared 12–70% of mutations, consistent with likely secondary metastases. These results conflicted with pathologic assessment in 41.7% of cases (5/12 patients), all of whom were pathologically diagnosed with local metastases but genomically consistent with distinct primaries.…”

Molecular characteristics of multifocal esophageal squamous cell carcinomas to discriminate multicentric origin from intramural metastasis

“…Next, the index‐coded library samples were clustered on a cBot Cluster Generation System (Illumina, San Diego, CA, USA), and the DNA libraries were sequenced on an Illumina HiSeq 2000 system. The filtering of false mutation calling resulting from FFPE samples was performed based on our previous study [13].…”

“…Somatic single nucleotide variations (SNVs) were identified by MuTect [22], while somatic insertions and deletions (indels) were called using IndelRealigner and RealignerTargetCreator in GATK (v1.0.6076) [23]. High-confidence variants were identified through an in-house pipeline, as we have reported previously [13].…”

“…Some molecular biomarkers, such as TP53 mutations and p53 immunohistochemical expression, may be useful [7], but high levels of intratumor heterogeneity and use of a single biomarker may limit the ability to make convincing conclusions [8,9]. In recent years, several studies, including ours, have evaluated tumor origins and the heterogeneity of multiple cancers based on the genomic profile revealed by whole-genome sequencing (WGS) or whole-exome sequencing (WES) [10][11][12][13], but next-generation sequencing (NGS)-based assays have not yet been fully explored in uncovering the clone relationship of multifocal ESCCs. Additionally, immunotherapy has gradually become a new promising method for advanced ESCC [14,15], and neoadjuvant immunotherapy is manageable with an exciting complete response rate in locally advanced ESCC [16].…”