Genomic analysis of primary malignant melanoma of the esophagus.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21515-e21515
Author(s):  
Jingjing Li ◽  
Shi Yan ◽  
Wenyan Guan ◽  
Xiao Xiao ◽  
Bing Liu ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Somatic Mutations ◽  
Genome Instability ◽  
Mapk Signaling ◽  
Primary Malignant Melanoma ◽  
Base Substitution ◽  
Pathway Enrichment Analysis ◽  
Driver Genes ◽  
Primary Tumors ◽  
Genetic Characteristics

e21515 Background: Primary malignant melanoma of the esophagus (PMME) is an exceedingly rare disease but behave more aggressively and have a poorer prognosis. No specific histopathological classification and therapy strategies have been established for this type of disease due to lack of both tumor biological and genetics perception to PMME. Methods: We performed whole exome sequencing on 29 dissections including 23 primary tumors and 6 metastatic lymph nodes from 18 PMME patients. The genetic characteristics including somatic mutations and copy number variation (CNV) of PMME were compared to 398 skin cutaneous melanoma (SKCM), 67 mucosal melanoma (MM) and 79 uveal melanoma (UVM). Using multi-region sequencing, we reconstructed the phylogenetic structure and inferred the evolutionary mode. Results: We found that PMME/MM have similar genomic patterns to SKCM but distinct from UVM. Frequently mutated driver genes such as MUC16, BRAF, NRAS, NF1, KMT2C, POLE, PTPRT, RANBP2 appeared in both SKCM and PMME/MM cohorts. Of note, pathway enrichment analysis using identified driver genes revealed that melanoma pathway and MAPK signaling pathway were among the top affected pathways in MM/PMME as well as in SKCM. UVR-associated single base substitution signature 7 (SBS7) was not a dominant signature (median: 0.17, range:0̃0.79) in PMME/MM but 99 percent (89/90) of them do have it. An overall concordant trend in genome instability was found between PMME and SKCM. Significant CNV events at arm level showed the similar changes in PMME and SKCM, including amplification regions of 1q, 6p, 7p, 8q, 15q, 20p and deletion of 10p, 10q, 11p. CDKN2A loss appeared as a shared focal event by PMME and SKCM. To elucidate the evolution trajectory of spatially separated samples, we also performed multi-region sequencing, and the phylogenetic analysis suggested that whole genome doubling (WGD) was an early and clonal event, which preceded the majority of somatic mutations and CNV. Most driver genes such as NF1, RANBP2 and MUC16 mutated after WGD except TP53. Above findings suggested that WGD might be capable of promoting ongoing genome instability and shaping the evolution in PMME. Moreover, parallel evolution of RANBP2 was recurrently observed indicating the existence of constraints and selection. Conclusions: Our data showed that PMME/MM exhibited genetic features very similar to SKCM so it might not be excluded from treatments currently used for common SKCM.

scholarly journals Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

2018 ◽  
Vol 116 (2) ◽  
pp. 619-624 ◽  
Author(s):  
Charles Li ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jungmin Choi ◽  
Weilai Dong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Metastatic Tumors ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Landscape ◽  
Recurrent Tumors ◽  
Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

scholarly journals SYS-Mut: Decoding the Functional Significance of Rare Somatic Mutations in Cancer

2021 ◽  
Author(s):  
Sirvan Khalighi ◽  
Peronne Joseph ◽  
Deepak Babu ◽  
Salendra Singh ◽  
Thomas LaFramboise ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Low Frequency ◽  
Gene Mutations ◽  
Tailored Therapy ◽  
Driver Genes ◽  
Therapeutic Targeting ◽  
Primary Tumors ◽  
Vast Number ◽  
Subsequent Application ◽  
Number Of Genes

Current tailored-therapy efforts in cancer are largely focused on a small number of highly recurrently-mutated driver genes but therapeutic targeting of these oncogenes remains challenging. On the other hand, the vast number of genes mutated infrequently across cancers have received less attention, in part, due to a lack of understanding of their biologic significance. Here we present SYS-Mut, a systems biology platform that can robustly infer the biologic consequences of somatic mutations by integrating routine multi-omic profiles in primary tumors. We established the accuracy of SYS-Mut by recapitulating the functional impact of known driver genes in PanCancer datasets. Subsequent application of SYS-Mut on low-frequency gene mutations in Head and Neck Cancers (HNSC), followed by molecular and pharmacogenetic validation, revealed the lipidogenic network as a novel therapeutic vulnerability in aggressive HNSC. SYS-Mut is thus a robust scalable framework that enables discovery of new targetable avenues in cancer.

scholarly journals Primary Malignant Melanoma of the Gallbladder: A Case Report and Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Mehmet Fatih Haskaraca ◽  
Mustafa Ozsoy ◽  
İsmail Özsan ◽  
Kamile Kurt
Keyword(s):  
Malignant Melanoma ◽  
Gallbladder Wall ◽  
Primary Malignant Melanoma ◽  
Epithelial Tumor ◽  
Primary Tumors ◽  
Surgical Specimen ◽  
Eosinophilic Cytoplasm ◽  
Atypical Cells ◽  
Histopathologic Evaluation ◽  
Melanoma Case

Malignant melanoma is characterized by the ability of diffuse metastases. Since the first report of an isolated malignant melanoma case of the gallbladder, it is already controversial whether isolated cases are metastatic or primary tumors. A 49-year-old woman appealed to the emergency unit because of abdominal pain. Ultrasonography revealed increased thickness of the gallbladder wall and a lesion with surrounding fluid sized 12 mm without acoustic shadow, which arose from the gallbladder wall and was consistent with a polyp. Histopathologic evaluation of the surgical specimen after laparoscopic cholecystectomy revealed malign epithelial tumor consisting of atypical cells with large eosinophilic cytoplasm and dense melanin pigment within the cytoplasm of the tumor cells. As no other focus was identified as a result of the evaluation, the patient was diagnosed with primary malignant melanoma of the gallbladder. In this paper, we aimed to define our treatment modality for a case with isolated malignant melanoma of the gallbladder.

scholarly journals Somatic mutations in adrenals from patients with primary aldosteronism not cured after adrenalectomy suggest common pathogenic mechanisms between unilateral and bilateral disease

2021 ◽  
Author(s):  
Inès Hacini ◽  
Kelly De Sousa ◽  
Sheerazed Boulkroun ◽  
Tchao Meatchi ◽  
Laurence Amar ◽  
...  
Keyword(s):  
Clinical Data ◽  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Adrenal Glands ◽  
Morphological Characteristics ◽  
Driver Genes ◽  
Genetic Characteristics ◽  
Aldosterone Production ◽  
Biochemical Cure ◽  
Lateralization Index

Objective: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension. Different germline and somatic mutations are found in aldosterone producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with APA; however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy as well as the histological and genetic characteristics of their adrenal glands. Design and Methods: Clinical data of 12 patients without biochemical cure were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2-guided NGS. Results: Patients with absent hormonal cure displayed longer duration of arterial hypertension and lower lateralization index of aldosterone production. In 10 patients, APA expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with our without hormonal cure. Somatic mutations in APA driver genes were identified in all CYP11B2 positive APA; CACNA1D mutations were the most frequent genetic abnormality. Conclusions: Patients with absent biochemical cure were diagnosed later and exhibited lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.

scholarly journals Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shumaila Sayyab ◽  
Anders Lundmark ◽  
Malin Larsson ◽  
Markus Ringnér ◽  
Sara Nystedt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Driver Genes ◽  
Protein Coding ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

scholarly journals Primary malignant melanoma of the lacrimal sac

2012 ◽  
Vol 2012 (aug09 1) ◽  
pp. bcr2012006349-bcr2012006349 ◽  
Author(s):  
Y.-J. Li ◽  
S.-J. Zhu ◽  
H. Yan ◽  
J. Han ◽  
D. Wang ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Primary Malignant Melanoma ◽  
Lacrimal Sac

scholarly journals Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Kristell Le Gal ◽  
Clotilde Wiel ◽  
Mohamed X. Ibrahim ◽  
Marcus Henricsson ◽  
Volkan I. Sayin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Malignant Melanoma ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Nuclear Dna ◽  
Human Melanoma ◽  
Oxygen Species ◽  
Lung Cancer Cell ◽  
Primary Tumors ◽  
Anti Cancer

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

scholarly journals Primary Malignant Melanoma of the Vagina without Metastasis: A Rare Case and Review of Literature

2020 ◽  
Author(s):  
Wilson Bizimana ◽  
Gloria Akimana ◽  
Arthur Semedo Insumbo ◽  
Hounayda Jerguigue ◽  
Rachida Latib ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Patient Survival ◽  
Rare Condition ◽  
Primary Malignant Melanoma ◽  
Imaging Features ◽  
Review Of Literature ◽  
Pelvic Magnetic Resonance Imaging ◽  
Improve Patient Survival ◽  
Appropriate Treatment ◽  
Improve Patient

AbstractMalignant melanoma of vagina is a rare condition. Its histogenesis has been debated and the positive diagnosis is based on immunohistochemistry. Pelvic magnetic resonance imaging remains the gold standard for assessing locoregional extension status and post-treatment surveillance of melanoma of vagina. The observation concerned a 53-year-old woman with no specific history who presented a primary malignant melanoma of vagina without secondary locations. To date, the case is the second one reported in the literature. Early diagnosis of the malignant melanoma of vagina may improve patient survival because late diagnoses are punctuated by poor prognosis. We have presented epidemiological with etiopathogenic characteristics and described all imaging features to stage the tumor and to conduct the appropriate treatment.

scholarly journals Genomic alterations caused by HPV integration in a cohort of Chinese endocervical adenocarcinomas

2021 ◽  
Author(s):  
Wenhui Li ◽  
Wanjun Lei ◽  
Xiaopei Chao ◽  
Xiaochen Song ◽  
Yalan Bi ◽  
...  
Keyword(s):  
Copy Number ◽  
Somatic Mutations ◽  
Hpv Infection ◽  
Copy Number Variations ◽  
Cervical Adenocarcinoma ◽  
Structural Variations ◽  
Driver Genes ◽  
Genetic Changes ◽  
Genomic Changes ◽  
Whole Exome

AbstractThe association between human papillomavirus (HPV) integration and relevant genomic changes in uterine cervical adenocarcinoma is poorly understood. This study is to depict the genomic mutational landscape in a cohort of 20 patients. HPV+ and HPV− groups were defined as patients with and without HPV integration in the host genome. The genetic changes between these two groups were described and compared by whole-genome sequencing (WGS) and whole-exome sequencing (WES). WGS identified 2916 copy number variations and 743 structural variations. WES identified 6113 somatic mutations, with a mutational burden of 2.4 mutations/Mb. Six genes were predicted as driver genes: PIK3CA, KRAS, TRAPPC12, NDN, GOLGA6L4 and BAIAP3. PIK3CA, NDN, GOLGA6L4, and BAIAP3 were recognized as significantly mutated genes (SMGs). HPV was detected in 95% (19/20) of patients with cervical adenocarcinoma, 7 of whom (36.8%) had HPV integration (HPV+ group). In total, 1036 genes with somatic mutations were confirmed in the HPV+ group, while 289 genes with somatic mutations were confirmed in the group without HPV integration (HPV− group); only 2.1% were shared between the two groups. In the HPV+ group, GOLGA6L4 and BAIAP3 were confirmed as SMGs, while PIK3CA, NDN, KRAS, FUT1, and GOLGA6L64 were identified in the HPV− group. ZDHHC3, PKD1P1, and TGIF2 showed copy number amplifications after HPV integration. In addition, the HPV+ group had significantly more neoantigens. HPV integration rather than HPV infection results in different genomic changes in cervical adenocarcinoma.

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