Dataset Information

Targeted ultra-deep sequencing unveils a lack of driver-gene mutations linking non-hereditary gastrointestinal stromal tumors and highly prevalent second primary malignancies: random or nonrandom, that is the question.

ABSTRACT: The association of non-hereditary (sporadic) gastrointestinal stromal tumors (GISTs) and second primary malignancies is known to be nonrandom, although the underlying molecular mechanisms remain unknown. In this study, 136 of 749 (18.1%) patients with sporadic GISTs were found to have additional associated cancers, with gastrointestinal and genitourinary/gynecologic/breast cancers being the most prevalent. Gene mutations in GISTs and their associated colorectal cancers (CRCs) (n=9) were analyzed using a panel of 409 cancer-related genes, while a separate group of 40 sporadic CRCs not associated with GISTs served as controls. All 9 of the GISTs had either KIT (8 of 9) or PDGFRA (1 of 9) mutations that were not present in their associated CRCs. Conversely, all but one of the 9 GIST-associated CRCs exhibited an APC mutation, a TP53 mutation or both, while none of their corresponding GISTs harbored either APC or TP53 mutations. The genetic profile of CRCs with and without associated GISTs did not differ. Although population-based studies and case series worldwide, including ours, have unanimously indicated that the GIST-CRC association is nonrandom, our targeted ultra-deep sequencing unveiled a lack of driver-gene mutations linking sporadic GISTs to highly prevalent second primaries. Further studies are needed to elucidate other genetic alterations that may be responsible for this puzzling contradiction.

SUBMITTER: Lai BR

PROVIDER: S-EPMC5347768 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Targeted ultra-deep sequencing unveils a lack of driver-gene mutations linking non-hereditary gastrointestinal stromal tumors and highly prevalent second primary malignancies: random or nonrandom, that is the question.

Lai Bo-Ru BR Wu Yu-Tung YT Kuo Yung-Chia YC Hsu Hung-Chih HC Chen Jen-Shi JS Chen Tse-Ching TC Wu Ren-Chin RC Chiu Cheng-Tang CT Yeh Chun-Nan CN Yeh Ta-Sen TS

Oncotarget 20161201 50

The association of non-hereditary (sporadic) gastrointestinal stromal tumors (GISTs) and second primary malignancies is known to be nonrandom, although the underlying molecular mechanisms remain unknown. In this study, 136 of 749 (18.1%) patients with sporadic GISTs were found to have additional associated cancers, with gastrointestinal and genitourinary/gynecologic/breast cancers being the most prevalent. Gene mutations in GISTs and their associated colorectal cancers (CRCs) (n=9) were analyzed ...[more]

PMID: 27806309

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Project description:Adult diffuse gliomas commonly recur regardless of therapy. As recurrence typically arises from the peritumoral edema adjacent to the resected bulk tumor, the profiling of somatic mutations from infiltrative malignant cells within this critical, unresected region could provide important insights into residual disease. A key obstacle has been the inability to distinguish between next-generation sequencing (NGS) noise and the true but weak signal from tumor cells hidden among the noncancerous brain tissue of the peritumoral edema. Here, we developed and validated True2 sequencing to reduce NGS-associated errors to <1 false positive/100 kb panel positions while detecting 97.6% of somatic mutations with an allele frequency ≥0.1%. True2 was then used to study the tumor and peritumoral edema of 22 adult diffuse gliomas including glioblastoma, astrocytoma, oligodendroglioma, and NF1-related low-grade neuroglioma. The tumor and peritumoral edema displayed a similar mutation burden, indicating that surgery debulks these cancers physically but not molecularly. Moreover, variants in the peritumoral edema included unique cancer driver mutations absent in the bulk tumor. Finally, analysis of multiple samples from each patient revealed multiple subclones with unique mutations in the same gene in 17 of 22 patients, supporting the occurrence of convergent evolution in response to patient-specific selective pressures in the tumor microenvironment that may form the molecular foundation of recurrent disease. Collectively, True2 enables the detection of ultralow frequency mutations during molecular analyses of adult diffuse gliomas, which is necessary to understand cancer evolution, recurrence, and individual response to therapy.SignificanceTrue2 is a next-generation sequencing workflow that facilitates unbiased discovery of somatic mutations across the full range of variant allele frequencies, which could help identify residual disease vulnerabilities for targeted adjuvant therapies.

Dataset Information

Targeted ultra-deep sequencing unveils a lack of driver-gene mutations linking non-hereditary gastrointestinal stromal tumors and highly prevalent second primary malignancies: random or nonrandom, that is the question.

Publications

Targeted ultra-deep sequencing unveils a lack of driver-gene mutations linking non-hereditary gastrointestinal stromal tumors and highly prevalent second primary malignancies: random or nonrandom, that is the question.

Similar Datasets

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