A case description of pulmonary enteric adenocarcinoma with KRAS G12D mutation.
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ABSTRACT:
SUBMITTER: Fan F
PROVIDER: S-EPMC10721983 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
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A case description of pulmonary enteric adenocarcinoma with <i>KRAS</i> G12D mutation.
Quantitative imaging in medicine and surgery 20230915 12
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Project description:ObjectivesThere is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.MethodsThe exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.ResultsA total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).ConclusionsThe KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.
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Project description:Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolar epithelial type II (AT2) cells1. Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour.
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Project description:BackgroundPulmonary enteric adenocarcinoma (PEAC) has distinctive clinical outcomes, radiographic, pathological and molecular characteristics. The prognosis of patients with PEAC was poor. However, molecular profiles and therapeutic biomarkers of PEAC remain elusive.MethodsIn the present study, the hospitalized patients with PEAC admitted to Tongji Hospital in Wuhan from January 1, 2014 to November 20, 2020 were retrospectively enrolled and followed until December 10, 2020. Comprehensive genomic profiling of tumor tissue from the PEAC patients were performed and compared with lung adenocarcinoma, colorectal cancer and metastatic colorectal carcinoma. Tumor immune microenvironment analysis were evaluated.ResultsThere were 10 patients with PEAC enrolled. 70% of patients were male and the median age of onset was 63 years (interquartile range, 55-72). There were six early-stage patients (Stage IA to IIB) and four stage IV patients. Molecular analysis revealed the most common gene mutations included TP53 (57%, 4/7) and KRAS (57%, 4/7) mutations. There were 40% mutations occurred in genes encoding receptor tyrosine kinases (RTKs). 100% of patients (8/8) were microsatellite stability (MSS). The median level of TMB was 6.0 (interquartile range, 4.5-7.0) mutations/Mb. Three of 10 patients showed low PD-L1 expression (tumor proportion score < 10%) and the others were PD-L1 negative. A small subset of CD8+, CD3+, CD68+ T cells were observed and were mainly distributed in the cancer stroma.ConclusionThis study demonstrated that PEAC was characterized by low-frequency RTK gene mutation, high KRAS mutation, low PD-L1 expression, low TMB, and low CD8+ T cells infiltration.
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Project description:A 78-year-old male patient presented with dyspnea, loss of appetite, and weight loss. Workup and imaging showed suspected malignant lung lesion. Biopsy was done and showed features of pulmonary enteric adenocarcinoma (PEAC). This is a very rare disease and its diagnosis is challenging.
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Project description:Primary pulmonary enteric adenocarcinoma (PEAC) is a rare invasive adenocarcinoma clinically similar to metastatic colorectal adenocarcinoma (MCRC). Although many studies have addressed the differential diagnosis of PEAC, few have described the treatment of PEAC, especially using immunotherapy. This report describes a 61-year-old man who presented initially with pain in the ribs. Pathological analysis of biopsy samples shows malignant tumors of the right pleura, and next-generation sequencing of 26 genes showed a KRAS gene mutation. Positron emission tomography-computed tomography (PET-CT) found no evidence of gastrointestinal malignancy. Due to multiple metastases, the patient could not undergo radical surgery. The patient was treated with a combination chemotherapy regimen of paclitaxel plus carboplatin, along with sindilizumab immunotherapy, but, after one cycle of treatment, the tumor showed a hyperprogressive state. The patient is still being monitored regularly. These findings indicate that chemotherapy combined with immunotherapy may be ineffective in the treatment of primary PEAC with positive driver genes.
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Project description:Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras(G12D), but not with oncogenic EGFR(L858R), caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras(G12D)-induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras(G12D)-mediated tumor progression, but reduced EGFR(L858R)-mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras(G12D)-driven mucinous pulmonary adenocarcinoma.
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Project description:Pulmonary enteric adenocarcinoma (PEAC) is a rare variant of lung adenocarcinoma first described in the early 1990s in a lung tumour with overlapping lung and small intestine features. It is a rare tumour with fewer than 300 cases described in the published literature and was only formally classified in 2011. Given these characteristics the diagnosis is challenging, but even more so in a patient with prior gastrointestinal malignancy. A 68-year-old Caucasian female presented with a cough and was found to have a right upper lobe mass. Her history was significant for a pT3N1 colon adenocarcinoma. The resected lung tumour showed invasive lung adenocarcinoma but also features of colorectal origin. Immuno-stains were strongly and diffusely positive for lung and enteric markers. Multi-region, whole-exome sequencing of the mass and archival tissue from the prior colorectal cancer showed distinct genomic signatures with higher mutational burden in the PEAC and very minimal overlap in mutations between the two tumours. This case highlights the challenge of diagnosing rare lung tumours, but more specifically PEAC in a patient with prior gastro-intestinal cancer. Our use of multi-region, next-generation sequencing revealed distinct genomic signatures between the two tumours further supporting our diagnosis, and evidence of PEAC intra-tumour heterogeneity.
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Project description:BackgroundCombined small cell lung cancer (CSCLC) is rarely reported, which accounting for only 2% to 5% of all lung cancers. And enteric adenocarcinoma is also a rare subtype of non-small cell lung cancer (NSCLC) whose histomorphology is very similar to lung metastatic colorectal cancer.Case descriptionWe report a case with both small cell lung cancer (SCLC) and enteric adenocarcinoma for the first time. The patient was admitted to our hospital due to the left lung mass after a routine examination. She underwent computed tomography scan and needle biopsy, which showed the tumor consisted of two different components (70% SCLC and 30% enteric adenocarcinoma). The mixed density nodules were also observed in the right lung's lower lobe, and positron emission tomography-computed tomography (PET-CT) showed an increase of standard uptake value (SUV) greater than 2.5 in the right lung. Imaging and pathology experts agreed that the nodules of right lung were metastatic lesions after multi-disciplinary treatment (MDT). Considering the epidermal growth factor receptor (EGFR) p.L861Q mutation, the patient received gefitinib and EP chemotherapy, and she responded well to the combination therapy. At last follow-up, the progression-free survival (PFS) reached 11 months, and the adverse effects were clinically acceptable and tolerable.ConclusionsThis case report provides direct evidence for EGFR-tyrosine kinase inhibitor (TKI) and EP chemotherapy is effective and useful in the treatment of CSCLC patients with enteric adenocarcinoma.
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Project description:BackgroundLinear nevus sebaceous syndrome (LNSS) is a multisystem disorder that includes nevus sebaceous and central nervous system, ocular and skeletal anomalies. We report the first case of a KRAS G12D mosaic mutation in a patient diagnosed with LNSS.Case presentationA 3-month-old female with a clinical diagnosis of LNSS presented with intermittent epilepsy. Her mother carefully collected a skin lesion sample from scratched-off scurf obtained from the patient's nails. DNA was extracted, and long-range PCR was performed to amplify the KRAS gene, which was then analyzed by next-generation sequencing. The results revealed the presence of a low-level heterozygous mutation in the KRAS gene (c.35C>T; p.G12D, 5 %).ConclusionsThese findings suggest that the KRAS somatic mosaic mutation in this patient may have caused her skin and eye lesions and epilepsy. With this correct diagnosis, the infant can be effectively treated.
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Project description:Despite advancements in targeted and immunotherapies, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas, squamous cell carcinoma and large cell carcinoma. KRAS is commonly mutated in adenocarcinomas, with the most common point mutation being G12C (39%), followed by G12V (21%), G12D (17%), and G12A (10%). Notably, while KRASG12C is the most prevalent mutation in adenocarcinoma among former or current smokers (42%), KRASG12D is most common in patients who have never smoked (56%) [2]. Because nonsmokers have poorer prognosis, and mostly lack response to immunotherapy, we interrogated the immune changes in a previously described genetically engineered model of KrasG12D driven lung cancer. In this murine model, oncogenic Kras expression can be controlled genetically in the lung, allowing activation of oncogenic KrasG12D to initiate tumor growth, depletion of KrasG12D for tumor eradication, and re-activation of KrasG12D to model relapse. We demonstrate a KrasG12D dependent regulation of the tumor microenvironment depends on secreted factors derived from epithelial cells expressing oncogenic Kras, which regulates lung fibroblasts. Fibroblast derived secreted factors in turn drive an immune suppressive and tumor promoting phenotype in the lung, specifically through the polarization of macrophages. The identification of this oncogenic Kras-dependent secretome that supports lung tumor growth through crosstalk with the microenvironment provides new targets to develop alternative strategies for co-targeting KRAS mutant lung disease with Kras inhibitors or for treating recurring lung tumors.
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