pubmed > TP53 > frequently mutated

Immunohistochemical staining patterns of p53 predict the mutational status of TP53 in oral epithelial dysplasia.
Next-generation sequencing of oral squamous cell carcinoma (OSCC) has revealed TP53 as the most frequently mutated gene in OSCC mutually exclusive with human papillomavirus infection. Oral epithelial dysplasia (OED) is defined as a precancerous lesion of OSCC by the current World Health Organization (WHO) classification; therefore, it is assumed that TP53 mutations occur in early precancerous conditions such as OED. Here, we conducted an integrated analysis of TP53, including whole coding sequencing of TP53, FISH analysis of the 17p13.1 locus, and immunohistochemical analysis for p53 (p53-IHC), in 40 OED cases. We detected 20 mutations in 16 (40%) OED cases, and four cases, each harbored two mutations. FISH analysis revealed six of 24 cases (25%) had a deletion on 17p13.1, and four cases had concurrent TP53 mutations and 17p13.1 deletion (2-hit). Also, the increased frequency of TP53 mutations in higher degrees of OED implies acquisition of the mutation is a major event toward OSCC. p53-IHC revealed that overall cases could be categorized into four patterns that correlate well with the mutational status of TP53. Especially, two patterns, broad p53 expression type (pattern HI) and p53 null type (pattern LS), strongly correlated with a missense mutation and nonsense mutation, respectively. Furthermore, seven of the 40 cases progressed to SCC, and six of these seven cases presented pattern HI or LS. Therefore, patterns HI and LS have a high risk for malignant transformation if excisional treatment is not performed irrespective of the dysplasia grade. Although the current WHO classification mainly focuses on morphological criteria for the diagnosis of OED, interobserver discrepancy appears in some instances of the OED diagnosis. Our immunohistochemical analysis supports a more accurate pathological diagnosis for OED in cases of low dysplastic changes or of differential diagnosis with non-dysplastic lesions.
Publication Date: 2021-08-19
Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

Genomic landscape and tumor mutation burden analysis of Chinese patients with sarcomatoid carcinoma of the head and neck.
Sarcomatoid carcinoma (SC) of the head and neck (HN) is a rare disease that has both sarcomatoid and cancerous components. The genetic background and mechanisms of tumorigenesis remain largely unrevealed, and the progress of precision therapy has been limited. Targeted DNA-based next-generation sequencing (NGS) was performed by a 539 genes panel of pan-cancer in 12 patients with SC of the HN to identify their genetic alterations and investigate clinically actionable mutations for use in precision treatment. TP53 was identified as the most frequently mutated gene. Genes related to the cell cycling, chromatin remodeling and histone modification were found to be frequently mutated in patients with SC of the HN. Alterations in receptor tyrosine kinases (RTKs) were also found in six patients. In addition, four patients had mutations in members of the downstream RAS and PI3-kinase pathways, PIK3CA was identified as the most frequently mutated gene in this pathway. The tumor mutation burden (TMB) value ranged from 0.71 to 14.71 per megabase, with a median of 4.34. The TMB value of PIK3CA mutation patients was significantly higher than that of PIK3CA wild-type patients. This was the first study to investigate genomic alterations specifically in Chinese patients with SC of the HN. Our research results showed that 10 out of 12 patients can match the targeted therapies or immunotherapy currently available in clinical practice or active clinical trials, suggesting precision therapy has the potential utility to improve the long-term prognosis for patients with the rare disease. Due to the small number of patients in this study, the findings need to be validated in a larger cohort.
Publication Date: 2021-08-10
Journal: Oral oncology

Subtyping of head and neck squamous cell cancers based on immune signatures.
Although head and neck squamous cell cancer (HNSCC) is one of the cancer types in which immune checkpoint inhibitors (ICIs) has achieved a certain success, only a subset of HNSCC patients respond to ICIs. Thus, identification of HNSCC subtypes responsive to ICIs is crucial. Using hierarchical clustering, we identified three subtypes of HNSCC, termed Immunity-H, Immunity-M, and Immunity-L, based on the enrichment scores of 28 immune cells generated by the single-sample gene-set enrichment analysis of transcriptome data. We demonstrated that this subtyping method was stable and producible in four different HNSCC cohorts. Immunity-H had the highest levels of immune infiltrates and PD-L1 expression, lowest levels of stemness, intratumor heterogeneity and genomic instability, and favorable prognosis. In contrast, Immunity-L had the lowest levels of immune infiltrates and PD-L1 expression, highest levels of stemness, intratumor heterogeneity and genomic instability, and unfavorable prognosis. We found that somatic copy number alteration had a significant negative association with anti-tumor immunity in HNSCC, while tumor mutation burden showed no significant association. TP53, COL11A1, NSD1, and PKHD1L1 were more frequently mutated in Immunity-H versus Immunity-L, and their mutations were associated with increased immune signatures in HNSCC. Besides immune-related pathways, many stromal and oncogenic pathways were highly enriched in Immunity-H, including cell adhesion molecules, focal adhesion, ECM-receptor interaction, calcium signaling, MAPK signaling, apoptosis, VEGF signaling, and PPAR signaling. The high levels of PD-L1 expression and immune infiltration in Immunity-H indicate that this subtype responds best to ICIs. Our study recaptures the immunological heterogeneity in HNSCC and provide clinical implications for the immunotherapy of HNSCC.
Publication Date: 2021-08-01
Journal: International immunopharmacology

Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells.
Asparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.
Publication Date: 2021-07-17
Journal: Cell death & disease

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer.
Mutations in hereditary breast cancer genes play an important role in the risk for cancer. Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome. A total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001). Hereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.
Publication Date: 2021-07-02
Journal: Breast cancer research and treatment

[Well differentiated grade 3 gastroenteropancreatic neuroendocrine tumors:new insights into diagnosis and therapeutic strategy].
Gastroenteropancreatic neuroendocrine tumor G3(GEP-NET G3) is a novel subtype of neuroendocrine neoplasms proposed in 2019,which has unique biological behavior characteristics. However,there are still many challenges and controversies in its diagnosis and treatment. There are obvious differences between GEP-NET G3 and neuroendocrine carcinoma (NEC) in genetic alterations and molecular profiles. The most frequently mutated genes in NET G3 are MEN1,DAXX/ATRX,while in NEC,TP53 and Rb are the most frequently mutated genes. Currently,the mainstream view is that NET G3 and NEC are two distinct diseases with different genetic backgrounds,and NET G3 will not develop into NEC. Several clinical and pathological factors should be considered to distinguish GEP-NET G3 and NEC,which including patients' medical history,histopathological morphology of neoplasms,Ki-67 index,immunohistochemical results of TP53,Rb,DAXX/ATRX and other markers. Multidisciplinary treatment,including radical resection,chemotherapy,targeted therapy,peptide receptor radionuclide therapy,immunotherapy should be applied in patients with GEP-NET G3. Overall,given its relatively indolent biological behavior,the therapeutic strategy should be more actively. Although the cure strategy of NET G3 has many similarities with NET G1/2,it is completely different from NEC. 胃肠胰G3级神经内分泌瘤(NET G3)是2019年提出的一种新的神经内分泌肿瘤的亚群,具有独特的生物学行为特征,其诊断和治疗尚存在诸多难点和争议之处。胃肠胰NET G3与神经内分泌癌(NEC)在驱动基因及疾病起源上呈现明显差异,NET中突变频率最高的基因为MEN1、DAXX/ATRX等,而NEC中则为TP53和Rb。目前主流观点认为,NET G3与NEC是具有不同遗传背景的两种疾病,NET G3不会进展为NEC。胃肠胰NET G3与NEC的鉴别诊断需结合患者病史、肿瘤组织病理学形态、Ki-67指数、DAXX/ATRX、TP53和Rb等指标的免疫组化染色结果等综合考虑。胃肠胰NET G3的治疗方式包括手术、化疗、靶向治疗、肽受体放射性核素治疗、免疫治疗等。总体而言,鉴于NET G3相对温和的生物学行为,对于其治疗应持积极态度,采用以手术为主的综合治疗方案,部分治疗策略可参考NET G1或G2,但与NEC截然不同。.
Publication Date: 2021-07-02
Journal: Zhonghua wai ke za zhi [Chinese journal of surgery]

Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.
Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR. Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles. Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR. Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR. Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.
Publication Date: 2021-06-27
Journal: Breast cancer research and treatment

Shifting the paradigms for tumor suppression: lessons from the p53 field.
The TP53 gene continues to hold distinction as the most frequently mutated gene in cancer. Since its discovery in 1979, hundreds of research groups have devoted their efforts toward understanding why this gene is so frequently selected against by tumors, with the hopes of harnessing this information toward the improved therapy of cancer. The result is that this protein has been meticulously analyzed in tumor and normal cells, resulting in over 100,000 publications, with an average of 5000 papers published on p53 every year for the past decade. The journey toward understanding p53 function has been anything but straightforward; in fact, the field is notable for the numerous times that established paradigms not only have been shifted, but in fact have been shattered or reversed. In this review, we will discuss the manuscripts, or series of manuscripts, that have most radically changed our thinking about how this tumor suppressor functions, and we will delve into the emerging challenges for the future in this important area of research. It is hoped that this review will serve as a useful historical reference for those interested in p53, and a useful lesson on the need to be flexible in the face of established paradigms.
Publication Date: 2021-06-10
Journal: Oncogene

Targeted DNA profiling and the prevalence of NTRK aberrations in Chinese patients with head and neck cancer.
Head and neck cancers are aggressive epithelial tumours that are recognised as being particularly challenging to treat. Here, we report the targeted DNA profiling and the prevalence of neurotrophic-tropomyosin receptor tyrosine kinase gene (NTRK) aberrations in Chinese patients with head and neck cancers. Samples of 127 patients with head and neck cancer were retrospectively analysed. Profiling was performed by next-generation sequencing of the 1021-gene panel with tumour tissue and matched peripheral blood control samples. This study was inspired by the outcome benefit of a parotid cancer patient harbouring ETV6-NTRK3 fusion, who received crizotinib treatment and achieved a 2-year progression-free survival. Genomic profiling of 127 patients with head and neck cancers indicated that TP53 is the most frequently mutated gene both in our cohort and in The Cancer Genome Atlas (TCGA) database. A higher prevalence of NTRK genetic aberrations (7.9%, 10/127), including NTRK fusion (3.1%) and mutation, was observed in our population than in TCGA. The most common fusion was the ETV6-NTRK3. Compared to the NTRK-wt group, the NTRK aberration group had more APC and PTPRD aberrations (p < 0.05). NTRK fusion was also associated with lower tumour mutation burden (TMB) (p < 0.05). TP53 and LRP1B mutations were significantly associated with higher TMB (both p < 0.01), which may be potential markers of immunotherapy. This is the first study to report targeted DNA profiling of Chinese patients with head and neck cancers. As NTRK genetic aberrations are more common in this Chinese population, the efficacy of NTRK inhibitors should be studied further.
Publication Date: 2021-06-08
Journal: Oral oncology

Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.
Publication Date: 2021-05-17
Journal: Journal of hepatology

TP53 mutation and MET amplification in circulating tumor DNA analysis predict disease progression in patients with advanced gastric cancer.
Gastric cancer (GC) is a heterogeneous disease that encompasses various molecular subtypes. The molecular mutation characteristics of circulating tumor DNA (ctDNA) in advanced gastric cancer (AGC), especially the clinical utility of TP53 mutation and MET amplification in ctDNA need to be further explored. The aim of this study was mainly to assess the clinical utility of TP53 mutation and MET amplification in ctDNA as biomarkers for monitoring disease progression of AGC. We used multigene NGS-panel technology to study the characteristics of ctDNA gene mutations and screen the key mutant genes in AGC patients. The Kaplan-Meier method was used to calculate the survival probability and log-rank test was used to compare the survival curves of TP53 mutation and MET amplification in ctDNA of AGC patients. The survival time was set from the blood test time to the follow-up time to observe the relationship between the monitoring index and tumor prognosis. We performed mutation detection on ctDNA in 23 patients with AGC and identified the top 20 mutant genes. The five most frequently mutated genes were TP53 (55%), EGFR (20%), ERBB2 (20%), MET (15%) and APC (10%). TP53 was the most common mutated gene (55%) and MET had a higher frequency of mutations (15%) in our study. Kaplan-Meier analysis showed that patients with TP53 mutant in ctDNA had shorter overall survival (OS) than these with TP53 wild ( TP53 and MET are the two common frequently mutant genes in ctDNA of AGC patients.TP53 mutation and MET amplification in ctDNA could predict disease progression of AGC patients.
Publication Date: 2021-05-08
Journal: PeerJ

Clinicopathologic and genetic features of metaplastic breast cancer with osseous differentiation: a series of 6 cases.
Metaplastic breast cancer (MBC) comprises a heterogeneous group of tumors, of which MBC with osseous differentiation (MBC-OD) is extremely rare that only few cases have been reported. This study aimed to present the clinicopathologic and molecular features of MBC-OD. We collected 6 cases of MBC-OD from five different centers and described its clinicopathologic and molecular characteristics based on the next-generation sequencing. Another 11 cases from the literature were also reviewed to better characterize the tumor. The tumor primarily showed an osteosarcoma-like appearance, which composed of high cellularity with spindle cells and osteoblast-like cells producing coarse lace-like neoplastic bone (4/6) or osteoid matrix (6/6). 55 somatic mutations including 39 missenses (70.9%), 9 frameshifts (16.4%), 3 splice sites (5.5%), 3 in-frame InDels (5.5%) and 1 nonsense (1.8%) were identified. TP53 was the most frequently mutated genes (5/6, 83.3%), followed by RB1 (3/6, 50.0%), BCOR (2/6, 33.3%), MED12 (2/6, 33.3%), PIK3CA (2/6, 33.3%), and TET2 (2/6, 33.3%). Genetic alterations suggesting therapies with clinical benefit, including mTOR inhibitors, tyrosine kinase inhibitors (TKI), and poly-ADP ribose polymerase inhibitor (PARPi), were observed in five cases. The median follow-up was 21 months (range, 3-80 months). Local recurrence was observed in two cases and three patients displayed distant metastasis. Two patients died of the disease at 3 months and 7 months, respectively. Based on this series, MBC-OD is a highly aggressive breast tumor with osteosarcoma-like morphology and a high incidence of recurrent disease showing specific genetic profiles.
Publication Date: 2021-05-05
Journal: Breast cancer (Tokyo, Japan)

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer.
Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.
Publication Date: 2021-04-16
Journal: Scientific reports

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy.
Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.
Publication Date: 2021-04-07
Journal: The Journal of experimental medicine

Comprehensive genomic profiling and prognostic analysis of cervical gastric-type mucinous adenocarcinoma.
Gastric-type mucinous adenocarcinoma (GAS) is an uncommon cervical adenocarcinoma, which is not associated with human papillomavirus (HPV) infection. Compared with HPV-associated cervical adenocarcinoma, GAS has characteristics of larger volume, deep invasion, and easy to metastasize to distant sites. Also, GAS is typically resistant to chemo/radiotherapy. Few studies have reported the molecular genetic characteristics of GAS. In order to investigate the molecular genetic characteristics of GAS and reveal its possible pathogenesis, 15 GAS patients were enrolled from Peking University People's Hospital (2009-2019) and examined with next-generation sequencing (NGS). Based on the clinicopathologic feature analysis, we found that the presence of lymph node metastasis and extensive lymphovascular invasion were associated with poor survival outcomes of GAS (p = 0.0042 and p = 0.005, respectively). Based on the NGS testing, our results showed that the most frequently mutated gene was TP53 (8/15, 53.3%), followed by STK11, CDKN2A, and ARID1A. STK11 mutations were more frequent in well-differentiated GAS (33.3% vs. 0.0%, p = 0.026) and patients with extensive lymphovascular invasion (33.3% vs. 0.0%, p = 0.044). Survival analysis revealed that STK11 mutations were significantly associated with the poor prognosis of GAS (p = 0.01). Our results also showed that mutations in the target drug were detected in 53.3% of GAS patients. Patients with ERBB2 amplification (13.3%) presented the highest level of evidence according to OncoKB recommendations. These results indicate that the genomic alterations of GAS mainly involved the cell cycle and PI3K/AKT signaling pathways, and some therapeutic candidates were identified in GAS patients.
Publication Date: 2021-04-06
Journal: Virchows Archiv : an international journal of pathology

Precision medicine: preliminary results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT2) study.
Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling ( NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.
Publication Date: 2021-03-21
Journal: NPJ precision oncology

Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia.
Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.
Publication Date: 2021-03-18
Journal: Human pathology

Gene mutations of esophageal squamous cell carcinoma based on next-generation sequencing.
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore potential molecular targets in ESCC, we quantified the mutation spectrum and explored the relationship between gene mutation and clinicopathological characteristics and programmed death-ligand 1 (PD-L1) expression. Between 2015 and 2019, 29 surgically resected ESCC tissues and adjacent normal tissues from the Fourth Hospital of Hebei Medical University were subjected to targeted next-generation sequencing. The expression levels of PD-L1 were detected by immunohistochemistry. Mutational signatures were extracted from the mutation count matrix by using non-negative matrix factorization. The relationship between detected genomic alterations and clinicopathological characteristics and PD-L1 expression was estimated by Spearman rank correlation analysis. The most frequently mutated gene was TP53 (96.6%, 28/29), followed by NOTCH1 (27.6%, 8/29), EP300 (17.2%, 5/29), and KMT2C (17.2%, 5/29). The most frequently copy number amplified and deleted genes were CCND1/FGF3/FGF4/FGF19 (41.4%, 12/29) and CDKN2A/2B (10.3%, 3/29). By quantifying the contribution of the mutational signatures to the mutation spectrum, we found that the contribution of signature 1, signature 2, signature 10, signature 12, signature 13, and signature 17 was relatively high. Further analysis revealed genetic variants associated with cell cycle, chromatin modification, Notch, and Janus kinase-signal transducer and activator of transcription signaling pathways, which may be key pathways in the development and progression of ESCC. Evaluation of PD-L1 expression in samples showed that 13.8% (4/29) of samples had tumor proportion score ≥1%. 17.2% (5/29) of patients had tumor mutation burden (TMB) above 10 mut/Mb. All samples exhibited microsatellite stability. TMB was significantly associated with lymph node metastasis (r = 0.468, P = 0.010), but not significantly associated with PD-L1 expression (r = 0.246, P = 0.198). There was no significant correlation between PD-L1 expression and detected gene mutations (all P > 0.05). Our research initially constructed gene mutation profile related to surgically resected ESCC in high-incidence areas to explore the mechanism underlying ESCC development and potential therapeutic targets.
Publication Date: 2021-03-17
Journal: Chinese medical journal

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study.
Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use. We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months). Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology. Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse. The trial was registered at ( NCT01956552 ).
Publication Date: 2021-03-17
Journal: Genome medicine

Mucin 4 mutation is associated with tumor mutation burden and promotes antitumor immunity in colon cancer patients.
At present, immunotherapy is widely used for different mismatch repair (dMMR) or highly microsatellite instability (MSI-H) colorectal cancer patients, and tumor mutation burden (TMB) is a valuable independent predictor of response to immunotherapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immune cells in colon cancer remains unclear. In the present study, we analyzed somatic mutation data of colon cancer from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets, and found that 17 frequently mutated genes were occurred in both cohorts, including APC, TP53, TNN, KRAS, MUC16, MUC4 (mucin 4), SYNE1, FLG, FAT4, OBSCN, FAT3, RYR2, PIK3CA, FBXW7, DNAH11, MUC5B and ZFHX4. Interestingly, only MUC4 mutation was associated with higher TMB and patient clinical prognosis among the 17 mutated genes. Moreover, according to gene set enrichment analysis (GSEA) and the CIBERSORT algorithm, we revealed that MUC4 mutation activated signaling pathways involved in the immune system and enhanced the antitumor immune response. In conclusion, MUC4 may have important clinical implications for immune therapy of colon cancer.
Publication Date: 2021-03-15
Journal: Aging

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p 0 044(2)

62 7(2)

pten tp53(2)

tp53 mutation status(2)

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52 4(2)

2 6 33 3(1)

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5 664 0 8(1)

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27 8(1)

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ci 0 26-0 81(1)

n 4 63(1)

p 0 05(1)

fbfr2 13(1)

csmd3 muc16(1)

ctnnb1 14(1)

tp53 18(1)

smad4 ctnnb1(1)