Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes

PURPOSE: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. EXPERIMENTAL DESIGN: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS). RESULTS: Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P \u3c 0.0001). CONCLUSIONS: This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings

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Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process

Additional Primary Malignancies in Patients with Gastrointestinal Stromal Tumor (GIST): A Clinicopathologic Study of 260 Patients with Molecular Analysis and Review of the Literature.

BACKGROUND: The incidence of other primary neoplasms in gastrointestinal stromal tumor (GIST) patients is relatively high. Our aim was to better characterize the clinicopathologic and molecular relationships in a cohort of GIST patients. METHODS: All GIST patients with tumor samples sent for molecular testing were identified via electronic medical records. Clinicopathologic characteristics of GIST and additional primary malignancies were analyzed. RESULTS: Of 260 patients, 50 (19 %) had at least one additional primary malignancy. In 33 patients, separate primary neoplasms predated their GIST diagnosis and most commonly included: prostate (n = 9), breast (n = 8), and hematologic (n = 5). Renal (n = 4) and hematologic (n = 3) malignancies were the most frequent cancers identified after GIST diagnosis. The majority (8 of 12, 66 %) of malignancies diagnosed after GIST were found incidentally. Patients who developed other malignancies after GIST more often had KIT exon 11 mutations (100 vs. 66 %, P = 0.01). In comparison to patients with only GIST, patients with a second primary neoplasm of any chronology had GISTs with increased mitotic rate (≥5 per 50 high-power fields) (P = 0.0006). Literature review revealed colorectal cancer, gastric, prostate, renal, leukemia, and desmoid-type fibromatosis as the most common secondary neoplasms. CONCLUSIONS: Nineteen percent of GIST patients develop other malignancies. This is the first report to describe a relationship between additional primary malignancy and both mutation and mitotic rate of GIST. Although the basis of these relationships remains to be investigated, caution in the clinical management of GIST patients with additional lesions is warranted