Somatic alterations of NF1 in colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4066-4066
Author(s):  
Hiroyuki Arai ◽  
Andrew Elliott ◽  
Joanne Xiu ◽  
Jingyuan Wang ◽  
Francesca Battaglin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Characteristics ◽  
Small Subset ◽  
Ras Signaling ◽  
Egfr Inhibition ◽  
Ras Activation ◽  
Tumor Mutational Burden ◽  
Frequent Mutations ◽  
Somatic Alterations ◽  
Recombination Pathway

4066 Background: NF1 encodes neurofibromin, which is a key GTPase-activating protein that downregulates RAS activation. Inactivating mutations in NF1 result in sustained activation of RAS signaling, a key driver for development of colorectal cancer (CRC), and have been suggested to be a potential mechanism of resistance to EGFR inhibition in RAS-wild type (WT) CRC. Little is known about molecular characteristics of NF1-mutated (MT) CRC. Methods: Tumor profiles from 8150 CRC patients (pts) with available NF1 mutation status were retrospectively reviewed. NextGen sequencing by a customized 592-gene panel was performed. Microsatellite instability (MSI) / mismatch repair (MMR) status, tumor mutational burden (TMB) and PD-L1 expression were tested. Molecular profiles between NF1-MT and NF1-WT pts were compared. Results: Out of 8150 pts, 176 (2.2%) had somatic NF1 mutations with pathogenic or presumed pathogenic function. A higher NF1-MT frequency was observed in MSI-H/dMMR vs MSS/pMMR (13.5% vs 1.4%, p < 0.0001), in right-sided vs left sided (2.9% vs 1.8%, p < 0.01), and in RAS-WT vs RAS-MT (3.0% vs 1.4%, p < 0.0001). In MSS/pMMR tumors, no association with sidedness was observed (right: 1.3% vs left: 1.2%, NS). The most prevalent co-mutations with NF-1 were APC (63.2%), ARID1A (57.5%), TP53 (51.5%), KMT2D (32.9%) and KRAS (32.4%) in all cases, and APC (76.2%), TP53 (69.5%), KRAS (38.8%), ARID1A (34.4%) and FBXW7 (21.5%) in MSS/pMMR cases. POLE mutation was observed in 18.4% of NF1-MT/MSS/pMMR pts. Compared to NF1-WT pts, NF1-MT pts had more frequent mutations in ARID1A (All: 57.5% vs 23.3%, p < 0.0001; MSS/pMMR: 34.4% vs 15.2%, p < 0.05), and less frequent mutations in KRAS (All: 32.4% vs 49.0%, p < 0.0001; MSS/pMMR: 38.8% vs 50.3%, p < 0.05). Also, NF1-MT pts had more frequent alterations in homologous recombination pathway compared to NF1-WT pts (All: 39.8% vs 7.5%, p < 0.0001; MSS/pMMR: 17.5% vs 4.4%, p < 0.0001). Mean TMB was significantly greater in NF1-MT than NF1-WT (All: 48.9/Mb vs 10.0/Mb, p < 0.0001; MSS/pMMR: 48.3/Mb vs 8.2/Mb, p < 0.0001). Also, PD-L1 positivity was higher in NF1-MT compared to NF1-WT (All: 12.9% vs 3.6%, p < 0.0001; MSS/pMMR: 7.1% vs 2.6%, p < 0.05). Conclusions: While more frequent than in RAS-MT pts, NF1-MT CRC was a small subset in RAS-WT pts. NF1-MT was associated with alterations in chromatin remodeling and DNA damage response pathways, as well as elevated TMB and PD-L1 expression, which may provide alternative therapeutic strategies beyond EGFR inhibition.

BRCA mutations in metastatic colorectal cancer (mCRC) and response to chemotherapy.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 235-235
Author(s):  
Sophie Feng ◽  
Laith Al-Showbaki ◽  
Monika K. Krzyzanowska ◽  
Rebecca M. Prince ◽  
Tracy Stockley ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Series ◽  
Molecular Characteristics ◽  
Small Subset ◽  
Chemotherapy Response ◽  
First Line ◽  
Brca Mutations ◽  
Response To Chemotherapy ◽  
Brca 1 ◽  
The Impact

235 Background: Mutations in BRCA 1/2 are typically associated with breast, ovarian, pancreatic and prostate cancers. BRCA mutations have been reported in colorectal cancer in sporadic case series. Unlike other cancers, the significance of BRCA mutations in mCRC is not known. We report the prevalence and molecular characteristics associated with BRCA 1/2 mutations in mCRC, and investigate the impact of these mutations on chemotherapy response since both oxaliplatin (OX) and irinotecan (IRI) interfere with DNA repair pathways. Methods: The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) database was queried to identify mCRC patients (pts) harbouring BRCA 1/2 mutations. BRCA 1/2 mutations were detected using panel-based next generation sequencing (NGS) on archival tumour tissue. Clinical and molecular variables were collected, together with treatment outcomes. Results: Of 279 mCRC pts within the OCTANE database as of March 2019, 9 pts with BRCA 1/2 mutations were identified (3.2%): 4 BRCA 1 and 5 BRCA 2 mutations. Each patient had a unique variant with 8/9 missense mutations and 1/9 splicing error. Allele frequency ranged from 0.11 to 0.57. RAS or BRAF mutations were present in 67%. Common co-mutations included TP53 (56%), APC (56%), TSC1 (44%), ROS1 (33%) and ATM(33%). 2 pts were mismatch repair deficient. Median age was 48.5 years (range: 31-69 years), 56% males. 5 pts presented with de novo metastatic disease. First line OX-containing chemotherapy was administered to 4 pts, and IRI to 3 pts. 2 pts did not receive chemotherapy (1 had surgery only post-adjuvant OX, and 1 immunotherapy). Overall response rate (ORR) was 71%, with all pts achieving a partial response or stable disease. The median progression-free survival was 7.5 months (range: 1.8- 31.7 months) and median overall survival 68.5 months (range: 10.5- 68.5 months) respectively. Conclusions: BRCA 1/2 mutations are present in a small subset of mCRC pts. Pts with these mutations tend to be younger at diagnosis. BRCA 1/2 mutations are associated with favourable response to first line chemotherapy. Targeting BRCA 1/2 mutations may broaden treatment options for these patients.

scholarly journals A systems mechanism for KRAS mutant allele–specific responses to targeted therapy

2019 ◽  
Vol 12 (600) ◽  
pp. eaaw8288 ◽  
Author(s):  
Thomas McFall ◽  
Jolene K. Diedrich ◽  
Meron Mengistu ◽  
Stacy L. Littlechild ◽  
Kendra V. Paskvan ◽  
...  
Keyword(s):  
Genomic Medicine ◽  
Interaction Strength ◽  
Growth Factor Receptor ◽  
Mechanistic Explanation ◽  
Ras Signaling ◽  
Wild Type ◽  
Independent Manner ◽  
Egfr Inhibition ◽  
Ras Activation ◽  
Allele Specific

Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, that which encodes the G13D mutant protein (KRASG13D) behaves differently; for unknown reasons, KRASG13D CRC patients benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it contradicts the well-established mechanisms of EGFR signaling with regard to RAS mutations. Here, we identified a systems-level, mechanistic explanation for why KRASG13D cancers respond to EGFR inhibition. A computational model of RAS signaling revealed that the biophysical differences between the three most common KRAS mutants were sufficient to generate different sensitivities to EGFR inhibition. Integrated computation with experimentation then revealed a nonintuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interacted with and competitively inhibited NF1 drove wild-type RAS activation in an EGFR-independent manner, whereas KRASG13D weakly interacted with and could not competitively inhibit NF1 and, thus, KRASG13D cells remained dependent on EGFR for wild-type RAS activity. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.

scholarly journals Characterization of genomic alterations in Chinese colorectal cancer patients

2020 ◽  
Vol 51 (1) ◽  
pp. 120-129
Author(s):  
Wei Huang ◽  
Hui Li ◽  
Xiaoliang Shi ◽  
Minglin Lin ◽  
Cun Liao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Genomic Alteration ◽  
Molecular Characteristics ◽  
Tumor Differentiation ◽  
Cancer Genes ◽  
Exact Test ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Colorectal Cancer Patients

Abstract Objective Colorectal cancer is one of the most prevalent types of cancer worldwide. Right-sided and left-sided colorectal cancer (RCC and LCC) patients respond differently to treatment. We aimed to identify the different mutational profile between RCC and LCC and provided evidence for future precision therapy. Methods A total of 630 Chinese colorectal cancer patients, including 467 (74.1%) LCC and 163 (25.9%) RCC, were enrolled in this cohort. Both formalin-fixed paraffin-embedded tumor tissues and matching blood samples were collected and deep sequenced targeting 450 cancer genes for genomic alteration analysis. Tumor mutational burden was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher’s exact test. Results The most common mutated genes were TP53 (77.0%), APC (71.7%), KRAS (50.0%), SMAD4 (19.8%), PIK3CA (18.3%), FBXW7 (17.5%), TCF7L2 (12.5%), SOX9 (11.3%), LRP1B (10.8%), ARID1A (10.3%) and FAT4 (10.3%). The mutation frequencies of TP53 and APC in LCC were significantly higher than that of RCC, while the mutation frequency of PIK3CA was lower than that of RCC. Six gene fusions were specifically detected in RCC patients. Colorectal cancer sites were associated with gender (P = 4.15 × 10−5) and tumor differentiation (P = 0.059). In LCC, the gender-associated genes were FAT4, EP300, FAT1, LRP1, ARID1B, AR, FYN and TAF1, while in RCC, they were ARID1A, SMARCA4, LRP1 and GRIN2A. The mutations of 18 genes were associated with tumor differentiation (8 for LCC and 10 for RCC). High tumor mutational burden was more common in RCC. Our results implied more potential targeted drug therapy opportunities for RCC. Conclusion We describe the different molecular characteristics of LCC and RCC. Our result supported a better prognosis of RCC than LCC in Chinese colorectal cancer patients.

scholarly journals A Systems Mechanism for KRAS Mutant Allele Specific Responses to Targeted Therapy

2018 ◽  
Author(s):  
Thomas McFall ◽  
Jolene K Diedrich ◽  
Meron Mengistu ◽  
Stacy L Littlechild ◽  
Kendra V Paskvan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Genomic Medicine ◽  
Interaction Strength ◽  
Ras Signaling ◽  
Wild Type ◽  
Kras Mutations ◽  
Ras Pathway ◽  
Egfr Inhibition ◽  
Ras Activation ◽  
Allele Specific

A well-established genotype to phenotype relationship in genomic medicine is that activating KRAS mutations indicate resistance to anti-EGFR agents. We used a computational model of Ras signaling to investigate a confusing exception to this relationship whereby colorectal cancers with one specific, constitutively-active, mutant, KRAS G13D, respond to anti-EGFR agents. Our computational simulations of the biochemical processes that regulate Ras suggest EGFR inhibition reduces wild-type Ras activation in KRAS G13D mutant cancer cells more than in other KRAS mutant cancer cells. The model also reveals a non-intuitive, mutant-specific, dependency of wild-type Ras activation on EGFR. This dependency is determined by the interaction strength between a KRAS mutant and tumor suppressor neurofibromin. Our prospective experiments confirm this mechanism that arises from the systems-level regulation of Ras pathway signaling. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

scholarly journals Identification and validation of a miRNA-related expression signature for tumor mutational burden in colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lijun Xu ◽  
Qing Zheng
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Validation Cohort ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Immune Checkpoints ◽  
Positive Correlation ◽  
Expression Signature ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Abstract Background Tumor mutational burden (TMB) is a promising predictor, which could stratify colorectal cancer (CRC) patients based on the response to immune checkpoint inhibitors (ICIs). MicroRNAs (miRNAs) act as the key regulators of anti-cancer immune response. However, the relationship between TMB and miRNA expression profiles is not elucidated in CRC. Methods Differentially expressed miRNAs (DE miRNAs) between the TMBhigh group and the TMBlow group were identified for the CRC cohort of the TCGA database. In the training cohort, a miRNA-related expression signature for predicting TMB level was developed by the least absolute shrinkage and selection operator (LASSO) method and tested with reference to its discrimination, calibration, and decision curve analysis (DCA) in the validation cohort. Functional enrichment analysis of these TMB-related miRNAs was performed. The correlation between this miRNA-related expression signature and three immune checkpoints was analyzed. Results Twenty-one out of 43 DE miRNAs were identified as TMB-related miRNAs, which were used to develop a miRNA-related expression signature. This TMB-related miRNA signature demonstrated great discrimination (AUCtest set = 0.970), satisfactory calibration (P > 0.05), and clinical utility in the validation cohort. Functional enrichment results revealed that these TMB-related miRNAs were mainly involved in biological processes associated with immune response and signaling pathways related with cancer. This miRNA-related expression signature showed a median positive correlation with PD-L1 (R = 0.47, P < 0.05) and CTLA4 (R = 0.39, P < 0.05) and a low positive correlation with PD-1 (R = 0.16, P < 0.05). Conclusion This study presents a miRNA-related expression signature which could stratify CRC patients with different TMB levels.

scholarly journals Clinical, Pathological and Molecular Characteristics of Chilean Patients with Early-, Intermediate- and Late-Onset Colorectal Cancer

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 631
Author(s):  
Karin Alvarez ◽  
Alessandra Cassana ◽  
Marjorie De La Fuente ◽  
Tamara Canales ◽  
Mario Abedrapo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Age Of Onset ◽  
Late Onset ◽  
Molecular Characteristics ◽  
Family History Of Cancer ◽  
Molecular Features ◽  
Age Of Diagnosis ◽  
History Of ◽  
History Of Cancer

Colorectal cancer (CRC) is the second most frequent neoplasm in Chile and its mortality rate is rising in all ages. However, studies characterizing CRC according to the age of onset are still lacking. This study aimed to identify clinical, pathological, and molecular features of CRC in Chilean patients according to the age of diagnosis: early- (≤50 years; EOCRC), intermediate- (51–69 years; IOCRC), and late-onset (≥70 years; LOCRC). The study included 426 CRC patients from Clinica Las Condes, between 2007 and 2019. A chi-square test was applied to explore associations between age of onset and clinicopathological characteristics. Body Mass Index (BMI) differences according to age of diagnosis was evaluated through t-test. Overall (OS) and cancer-specific survival (CSS) were estimated by the Kaplan–Meier method. We found significant differences between the age of onset, and gender, BMI, family history of cancer, TNM Classification of Malignant Tumors stage, OS, and CSS. EOCRC category was characterized by a family history of cancer, left-sided tumors with a more advanced stage of the disease but better survival at 10 years, and lower microsatellite instability (MSI), with predominant germline mutations. IOCRC has shown clinical similarities with the EOCRC and molecular similarities to the LOCRC, which agrees with other reports.

scholarly journals Atypical, Non-V600 BRAF Mutations as a Potential Mechanism of Resistance to EGFR Inhibition in Metastatic Colorectal Cancer

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Benny Johnson ◽  
Jonathan M. Loree ◽  
Alexandre A. Jacome ◽  
Shehara Mendis ◽  
Muddassir Syed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Stable Disease ◽  
Kinase Activity ◽  
Class Ii ◽  
Activity Level ◽  
Class Iii ◽  
Braf Mutations ◽  
Egfr Inhibition ◽  
Mechanism Of Resistance

PURPOSE Atypical, non-V600 BRAF ( aBRAF) mutations represent a rare molecular subtype of metastatic colorectal cancer (mCRC). Preclinical data are used to categorize aBRAF mutations into class II (intermediate to high levels of kinase activity, RAS independent) and III (low kinase activity level, RAS dependent). The clinical impact of these mutations on anti-EGFR treatment efficacy is unknown. PATIENTS AND METHODS Data from 2,084 patients with mCRC at a single institution and from an external cohort of 5,257 circulating tumor DNA (ctDNA) samples were retrospectively analyzed. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. Statistical tests were two-sided. RESULTS BRAF mutations were harbored by 257 patients, including 36 with aBRAF mutations: 22 class III, 10 class II, four unclassified. For patients with aBRAF mCRC, median OS was 36.1 months, without a difference between classes, and median OS was 21.0 months for patients with BRAFV600E mCRC. In contrast to right-sided predominance of tumors with BRAFV600E mutation, 53% of patients with aBRAF mCRC had left-sided primary tumors. Concurrent RAS mutations were noted in 33% of patients with aBRAF mCRC, and 67% of patients had microsatellite stable disease. Among patients with aBRAF RAS wild-type mCRC who received anti-EGFR antibodies (monotherapy, n = 1; combination therapy, n = 10), no responses to anti-EGFR therapy were reported, and six patients (four with class III aBRAF mutations, one with class II, and one unclassified) achieved stable disease as best response. Median time receiving therapy was 4 months (range, 1 to 16). In the ctDNA cohort, there was an increased prevalence of aBRAF mutations and subclonal aBRAF mutations ( P < .001 for both) among predicted anti-EGFR exposed compared with nonexposed patients. CONCLUSION Efficacy of anti-EGFR therapy is limited in class II and III aBRAF mCRC. Detection of aBRAF mutations in ctDNA after EGFR inhibition may represent a novel mechanism of resistance.

scholarly journals Hematopoietic Cell Fate and the Initiation of Leukemic Properties in Primitive Primary Human Cells Are Influenced by Ras Activity and Farnesyltransferase Inhibition

2004 ◽  
Vol 24 (16) ◽  
pp. 6993-7002 ◽  
Author(s):  
Craig Dorrell ◽  
Katsuto Takenaka ◽  
Mark D. Minden ◽  
Robert G. Hawley ◽  
John E. Dick
Keyword(s):  
Cell Fate ◽  
Myeloid Cell ◽  
Early Event ◽  
Ras Signaling ◽  
Human Leukemia ◽  
Ras Pathway ◽  
Hematopoietic Malignancies ◽  
Ras Activation ◽  
Elevated Frequency ◽  
High Level

ABSTRACT The Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.

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