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Article ; Online: Computational methods and translational applications for targeted next-generation sequencing platforms.

Luthra, Anisha / Mastrogiacomo, Brooke / Smith, Shaleigh A / Chakravarty, Debyani / Schultz, Nikolaus / Sanchez-Vega, Francisco

Genes, chromosomes & cancer

2022 Volume 61, Issue 6, Page(s) 322–331

Abstract: During the past decade, next-generation sequencing (NGS) technologies have become widely adopted in cancer research and clinical care. Common applications within the clinical setting include patient stratification into relevant molecular subtypes, ... ...

Abstract	During the past decade, next-generation sequencing (NGS) technologies have become widely adopted in cancer research and clinical care. Common applications within the clinical setting include patient stratification into relevant molecular subtypes, identification of biomarkers of response and resistance to targeted and systemic therapies, assessment of heritable cancer risk based on known pathogenic variants, and longitudinal monitoring of treatment response. The need for efficient downstream processing and reliable interpretation of sequencing data has led to the development of novel algorithms and computational pipelines, as well as structured knowledge bases that link genomic alterations to currently available drugs and ongoing clinical trials. Cancer centers around the world use different types of targeted solid-tissue and blood based NGS assays to analyze the genomic and transcriptomic profile of patients as part of their routine clinical care. Recently, cross-institutional collaborations have led to the creation of large pooled datasets that can offer valuable insights into the genomics of rare cancers.
MeSH term(s)	Genomics/methods ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Neoplasms/pathology ; Precision Medicine/methods
Language	English
Publishing date	2022-02-03
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1018988-9
ISSN	1098-2264 ; 1045-2257
ISSN (online)	1098-2264
ISSN	1045-2257
DOI	10.1002/gcc.23023
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Article ; Online: Genomic profiling and metastatic risk in early-stage non-small cell lung cancer.

Fick, Cameron N / Dunne, Elizabeth G / Lankadasari, Manendra B / Mastrogiacomo, Brooke / Asao, Tetsuhiko / Vanstraelen, Stijn / Liu, Yuan / Sanchez-Vega, Francisco / Jones, David R

JTCVS open

2023 Volume 16, Page(s) 9–16

Language	English
Publishing date	2023-10-18
Publishing country	Netherlands
Document type	Editorial
ISSN	2666-2736
ISSN (online)	2666-2736
DOI	10.1016/j.xjon.2023.10.016
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Article ; Online: Genomic Characterization and Clinical Outcomes of Patients with Peritoneal Metastases from the AACR GENIE Biopharma Collaborative Colorectal Cancer Registry.

Cancer research communications

2024 Volume 4, Issue 2, Page(s) 475–486

Abstract: Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia ... ...

Abstract	Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment. Significance: Utilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM.
MeSH term(s)	Humans ; Female ; Colorectal Neoplasms/genetics ; Peritoneal Neoplasms/genetics ; Retrospective Studies ; Antineoplastic Agents/therapeutic use ; Colonic Neoplasms/drug therapy ; Rectal Neoplasms/drug therapy ; Genomics ; Registries
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-23-0409
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Article: The Emerging Importance of Tumor Genomics in Operable Non-Small Cell Lung Cancer.

Lengel, Harry B / Connolly, James G / Jones, Gregory D / Caso, Raul / Zhou, Jian / Sanchez-Vega, Francisco / Mastrogiacomo, Brooke / Isbell, James M / Li, Bob T / Liu, Yuan / Rekhtman, Natasha / Jones, David R

Cancers

2021 Volume 13, Issue 15

Abstract: During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of "targeted therapy" in advanced and metastatic disease. The use of specific tyrosine ...

Abstract	During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of "targeted therapy" in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as
Language	English
Publishing date	2021-07-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13153656
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Article ; Online: Lung resection after initial nonoperative treatment for non-small cell lung cancer.

The Journal of thoracic and cardiovascular surgery

2023

Abstract: Objectives: The study objectives were to assess the outcomes of lung resection in patients with non-small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival.: Methods: Patients ... ...

Abstract	Objectives: The study objectives were to assess the outcomes of lung resection in patients with non-small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival. Methods: Patients who underwent surgery (2010-2022) after initial nonoperative treatment at a single institution were identified from a prospectively maintained database. Exclusion criteria included metachronous cancer, planned neoadjuvant therapy, and surgery for diagnostic or palliative indications. Cox models were constructed for overall survival and event-free survival. Survival of patients with stage IV disease was compared with survival of a nonstudy cohort who did not undergo surgery. Results: In total, 120 patients met the inclusion criteria. Initial clinical stage was early stage in 16%, locoregionally advanced in 25%, and metastatic in 59% of patients. The indication for surgery was recurrence in 18%, local persistent disease in 23%, oligoprogression in 22%, and local control of oligometastatic disease in 38% of patients. Grade 3 or greater complications occurred in 5% of patients; 90-day mortality was 3%. Three-year event-free survival and overall survival were 39% and 73%, respectively. Male sex and lymphovascular invasion were associated with shorter event-free survival and overall survival; younger age and prior radiation therapy were associated with shorter overall survival. Patients with stage IV disease who received salvage lung resection had better overall survival than similar patients who received subsequent systemic therapy and no surgery. Conclusions: In this selected, heterogeneous population, lung resection after initial nonoperative treatment for non-small cell lung cancer was safe. Surgery as local consolidative therapy was associated with encouraging outcomes and should be considered for these patients.
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	3104-5
ISSN	1097-685X ; 0022-5223
ISSN (online)	1097-685X
ISSN	0022-5223
DOI	10.1016/j.jtcvs.2023.11.040
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Article: Preoperative clinical and tumor genomic features associated with pathologic lymph node metastasis in clinical stage I and II lung adenocarcinoma.

Caso, Raul / Connolly, James G / Zhou, Jian / Tan, Kay See / Choi, James J / Jones, Gregory D / Mastrogiacomo, Brooke / Sanchez-Vega, Francisco / Nguyen, Bastien / Rocco, Gaetano / Molena, Daniela / Sihag, Smita / Adusumilli, Prasad S / Bott, Matthew J / Jones, David R

NPJ precision oncology

2021 Volume 5, Issue 1, Page(s) 70

Abstract: While next-generation sequencing (NGS) is used to guide therapy in patients with metastatic lung adenocarcinoma (LUAD), use of NGS to determine pathologic LN metastasis prior to surgery has not been assessed. To bridge this knowledge gap, we performed ... ...

Abstract	While next-generation sequencing (NGS) is used to guide therapy in patients with metastatic lung adenocarcinoma (LUAD), use of NGS to determine pathologic LN metastasis prior to surgery has not been assessed. To bridge this knowledge gap, we performed NGS using MSK-IMPACT in 426 treatment-naive patients with clinical N2-negative LUAD. A multivariable logistic regression model that considered preoperative clinical and genomic variables was constructed. Most patients had cN0 disease (85%) with pN0, pN1, and pN2 rates of 80%, 11%, and 9%, respectively. Genes altered at higher rates in pN-positive than in pN-negative tumors were STK11 (p = 0.024), SMARCA4 (p = 0.006), and SMAD4 (p = 0.011). Fraction of genome altered (p = 0.037), copy number amplifications (p = 0.001), and whole-genome doubling (p = 0.028) were higher in pN-positive tumors. Multivariable analysis revealed solid tumor morphology, tumor SUVmax, clinical stage, SMARCA4 and SMAD4 alterations were independently associated with pathologic LN metastasis. Incorporation of clinical and tumor genomic features can identify patients at risk of pathologic LN metastasis; this may guide therapy decisions before surgical resection.
Language	English
Publishing date	2021-07-21
Publishing country	England
Document type	Journal Article
ISSN	2397-768X
ISSN	2397-768X
DOI	10.1038/s41698-021-00210-2
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Article ; Online: A germline SNP in BRMS1 predisposes patients with lung adenocarcinoma to metastasis and can be ameliorated by targeting c-fos.

Liu, Yuan / Chudgar, Neel / Mastrogiacomo, Brooke / He, Di / Lankadasari, Manendra B / Bapat, Samhita / Jones, Gregory D / Sanchez-Vega, Francisco / Tan, Kay See / Schultz, Nikolaus / Mukherjee, Semanti / Offit, Kenneth / Bao, Yongde / Bott, Matthew J / Rekhtman, Natasha / Adusumilli, Prasad S / Li, Bob T / Mayo, Marty W / Jones, David R

Science translational medicine

2022 Volume 14, Issue 665, Page(s) eabo1050

Abstract: About 50% of patients with early-stage, surgically resected lung cancer will develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence and to design innovative therapies to decrease this risk. Two primary ... ...

Abstract	About 50% of patients with early-stage, surgically resected lung cancer will develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence and to design innovative therapies to decrease this risk. Two primary isoforms of BRMS1, v1 and v2, are present in humans. Using next-generation sequencing of
MeSH term(s)	Animals ; Humans ; Mice ; Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/pathology ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Germ Cells ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Repressor Proteins/metabolism ; Polymorphism, Single Nucleotide
Chemical Substances	BRMS1 protein, human ; Repressor Proteins
Language	English
Publishing date	2022-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abo1050
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Article ; Online: Genomic mapping of metastatic organotropism in lung adenocarcinoma.

Lengel, Harry B / Mastrogiacomo, Brooke / Connolly, James G / Tan, Kay See / Liu, Yuan / Fick, Cameron N / Dunne, Elizabeth G / He, Di / Lankadasari, Manendra B / Satravada, Baby Anusha / Sun, Yichao / Kundra, Ritika / Fong, Chris / Smith, Shaleigh / Riely, Gregory J / Rudin, Charles M / Gomez, Daniel R / Solit, David B / Berger, Michael F /

Li, Bob T / Mayo, Marty W / Matei, Irina / Lyden, David C / Adusumilli, Prasad S / Schultz, Nikolaus / Sanchez-Vega, Francisco / Jones, David R

Cancer cell

2023 Volume 41, Issue 5, Page(s) 970–985.e3

Abstract: We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with ... ...

Abstract	We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.
MeSH term(s)	Humans ; Male ; Adenocarcinoma of Lung/genetics ; Mutation ; DNA Copy Number Variations ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Genomics ; DNA Helicases/genetics ; Nuclear Proteins/genetics ; Transcription Factors/genetics
Chemical Substances	SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; Nuclear Proteins ; Transcription Factors
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.03.018
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Article ; Online: Intraoperative opioid exposure, tumour genomic alterations, and survival differences in people with lung adenocarcinoma.

Connolly, James G / Tan, Kay See / Mastrogiacomo, Brooke / Dycoco, Joseph / Caso, Raul / Jones, Gregory D / McCormick, Patrick J / Sanchez-Vega, Francisco / Irie, Takeshi / Scarpa, Joseph R / Gupta, Hersh V / Adusumilli, Prasad S / Rocco, Gaetano / Isbell, James M / Bott, Matthew J / Fischer, Gregory W / Jones, David R / Mincer, Joshua S

British journal of anaesthesia

2021 Volume 127, Issue 1, Page(s) 75–84

Abstract: Background: Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated ... ...

Abstract	Background: Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied. Methods: Surgical patients (N=740) with pathological stage I-III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database. Results: On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24-0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02-1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways. Conclusions: Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.
MeSH term(s)	Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/mortality ; Adenocarcinoma of Lung/surgery ; Aged ; Analgesics, Opioid/administration & dosage ; Analgesics, Opioid/adverse effects ; Female ; Genomics/trends ; Humans ; Intraoperative Care/adverse effects ; Intraoperative Care/trends ; Lung Neoplasms/genetics ; Lung Neoplasms/mortality ; Lung Neoplasms/surgery ; Male ; Middle Aged ; Neoplasm Recurrence, Local/diagnosis ; Neoplasm Recurrence, Local/epidemiology ; Neoplasm Recurrence, Local/genetics ; Pain, Postoperative/prevention & control ; Prospective Studies ; Retrospective Studies ; Survival Rate/trends
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2021-06-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80074-0
ISSN	1471-6771 ; 0007-0912
ISSN (online)	1471-6771
ISSN	0007-0912
DOI	10.1016/j.bja.2021.03.030
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Article ; Online: Intraoperative ketorolac may interact with patient-specific tumour genomics to modify recurrence risk in lung adenocarcinoma: an exploratory analysis.

Connolly, James G / Scarpa, Joseph R / Gupta, Hersh V / Tan, Kay See / Mastrogiacomo, Brooke / Dycoco, Joseph / Caso, Raul / Jones, Gregory D / Sanchez-Vega, Francisco / Adusumilli, Prasad S / Rocco, Gaetano / Isbell, James M / Bott, Matthew J / Irie, Takeshi / McCormick, Patrick J / Fischer, Gregory W / Jones, David R / Mincer, Joshua S

British journal of anaesthesia

2021 Volume 127, Issue 3, Page(s) e82–e85

MeSH term(s)	Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/mortality ; Adenocarcinoma of Lung/pathology ; Adenocarcinoma of Lung/surgery ; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Biomarkers, Tumor/genetics ; Gene Regulatory Networks ; Genomics ; Humans ; Intraoperative Care ; Ketorolac/administration & dosage ; Ketorolac/adverse effects ; Lung Neoplasms/genetics ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Lung Neoplasms/surgery ; NF-E2-Related Factor 2/genetics ; Neoplasm Recurrence, Local ; Pneumonectomy/adverse effects ; Pneumonectomy/mortality ; Proto-Oncogene Proteins c-mdm2/genetics ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Biomarkers, Tumor ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Ketorolac (YZI5105V0L)
Language	English
Publishing date	2021-07-14
Publishing country	England
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80074-0
ISSN	1471-6771 ; 0007-0912
ISSN (online)	1471-6771
ISSN	0007-0912
DOI	10.1016/j.bja.2021.05.032
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