Search

Background: To study the prevalence of genetic mutations in patients with gastrointestinal stromal tumors (GIST) using next-generation sequencing at a tertiary care center in northern India. Methods: We performed genotypic analysis of histologically and immunohistochemically diagnosed GIST using Ion AmpliSeq Cancer Hotspot Panel v2 to identify mutations on resected biopsy samples. Results: In our cohort of 41 patients, we observed a variety of genetic mutations. The corresponding prevalence for those mutations was Tumour Protein 53 (TP53) 90, KIT Protooncogene receptor tyrosine kinase (KIT) 88, Platelet Derived Growth Factor Receptor (PDGFRA) 78, HRas Proto-oncogene (HRAS) 61, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) 56, Kristen rat sarcoma viral oncogene homolog (KRAS) 54, NRas Proconcogene GTPase (NRAS) 20, Cyclin-dependent kinase inhibitor 2A (CDKN2A) 15, and B-Raf proto-oncogene (BRAF) 7. Conclusion: GISTs host a variety of mutations that need to be further investigated for their interplay and overall effect on the Indian population so that we can tailor treatment for better prognosis. The incidence of GIST is rising worldwide. Advances in technology have made tailored theranostics a possibility in managing GIST. Detailed genetic presentation of GIST is still unclear. Next-generation sequencing has provided us with an excellent tool to prospectively analyze the genetic makeup of GIST and most of the tumors. The present study opens up a huge possibility for using molecular makers for risk stratification of GIST and for theranostics of such tumors. Keywords: GIST, KIT, NGS, Author(s): Trupti V. Deshpande (corresponding author) [1]; Pranav Dorwal [1]; Akshay A Anikhindi [2]; Nishant Tiwari [3]; Dharmendar Jain [1]; Simmi Mehra [1]; Ashok Vaid [4]; Vimarsh Raina [1] Introduction [...]

Background BRCA2 germline mutations are known to predispose carriers to various cancer types, including breast, ovarian, pancreatic and prostate cancer. An association with melanoma has also been reported. However, the full tumour spectrum associated with BRCA2 mutations, particularly in patients with other concurrent pathogenetic mutations, is unexplored. Case presentation We present a 70-year-old female patient with a pathogenic BRCA2 c.5946del variant. Over a period of 15 years, she has developed two independent breast cancers, well-differentiated liposarcoma, clear cell renal cell carcinoma and myeloproliferative neoplasia. This unusual tumour spectrum and the staggered occurrence of these tumours required multiple rounds of genetic testing and led to a delayed diagnosis of the BRCA2-associated tumour predisposition. In addition to the BRCA2 mutation, extended germline testing revealed an APC c.3920T > A variant and variants of unknown significance in the BRIP1 and ATR genes. The molecular analysis of the tumours revealed distinct profiles with differences in HRD status and in copy number variations, indicating no common origin. Conclusions Our case study revealed that the pathogenic BRCA2 c.5946del germline variant can be associated with an unusual tumour spectrum, which may lead to a delayed diagnosis of a hereditary tumour predisposition. Thus, upfront genetic testing using large multigene panels or whole-genome sequencing in encouraged, especially in cases with a prominent family history. Keywords: BRCA2 mutation, APC, Genetic testing, Whole-genome sequencing, Breast cancer, Renal cell carcinoma, Liposarcoma, Myeloproliferative neoplasia, Author(s): Elena Su[sup.1], Yann Christinat[sup.2], Thomas McKee[sup.3], Silvia Azzarello-Burri[sup.4], Wolfram Jochum[sup.4], Stefanie Fischer[sup.5] and Christian Rothermundt[sup.6] Background Mutations in the BRCA1 and BRCA2 genes have long been known to predispose [...]

* Context.--Mitochondria and mitochondrial DNA have been suggested to play a role in cancer initiation and progression. Knowledge of mitochondrial DNA could provide a breakthrough to advance cancer management. Objective.--To identify the mitochondrial DNA landscape in non-small cell lung carcinoma. Design.--The adenocarcinoma set consisted of 365 pairs of adenocarcinomas and normal lung tissues, whereas the metastasis set included 12 primary non-small cell carcinomas, 15 metastatic tumors, and their normal counterparts. Tumor-specific somatic variants were identified, and if a variant showed heteroplasmy, the proportion of minor alleles was evaluated. Variants with greater than 10% change in allele frequency between tumor and normal pairs were identified as 'heteroplasmic shifts.' Results.--Tumor-specific variants appeared throughout the whole mitochondrial genome, without a common hot spot. Distinct variant profiles were seen in 289 (79.18%) of all individual adenocarcinomas. The presence of a unique profile and the number and loading of heteroplasmic shifts in tumors increased with higher stage or lymph node metastasis, and were related to shorter survival. In the metastasis set, the primary tumor variants were generally found in metastatic tumors. Conclusions.--This study shows that somatic mitochondrial DNA mutations present with diverse locations and unique profiles in each individual tumor, implying their clinicopathologic utility. doi: 10.5858/arpa.2022-0175-OA, Alongside conventional studies investigating cancer genetics, interest in mitochondrial DNA (mtDNA) is increasing, with the anticipation that it will provide a genetic breakthrough. (1-8) Mitochondria perform several key functions, such [...]

Byline: K. W. Kim, J. Lee, E. D. Lee, S. Kim, S. S. Lee, H. T. Lim and S. H. Lee Keywords: Korea native black goat, genetic structure, genetic diversity, [...]

Medullary thyroid cancer (MTC) is the third most common thyroid cancer. RET (Rearranged in Transformation) gene mutations are considered as one of the major drivers of MTC. Vandetanib suppresses RET activity, and has shown promise in clinical trials. Unfortunately, acquired resistance to vandetanib has been observed in MTC, although the mechanism was largely unknown. We investigated the critical role of YAP (Yes-Associated Protein) on vandetanib resistance in MTC. For this, TT cells (medullary thyroid cancer cells) were treated with vandetanib for 3 months to generate a vandetanib-resistant cell line (TT-R). We investigated the role of YAP on vandetanib-resistance in TT-R cells by performing cell proliferation and colony formation assays, and examined the antitumor effects of YAP inhibitor and vandetanib in a mouse model of xenografted MTC. The TT-R cells displayed 6-fold higher [IC.sub.50] to vandetanib than the TT cells. Overexpression of YAP resulted in resistance to vandetanib, whereas knockdown of YAPre-sensitized the TT-R cells tovandetanib. The YAP inhibitor synergized with vandetanibon tumor inhibition. Our results suggest that YAP plays an important role in acquired resistance to vandetanib in MTC, providing basis for combating MTC with YAP inhibitor and vandetanib. Key words: medullary thyroid cancer, YAP, vandetanib, resistance. Le cancer medullaire de la thyroide (CMT) est le troisieme type de cancer de la thyroide le plus frequent. Des mutations du gene RET (Rearranged in Transformation) sont considerees comme l'un des principaux moteurs du CMT. Le vandetanib pourrait reprimer l'activite de RET et les essais cliniques ont montre des resultats prometteurs a cet egard. Malheureusement, le CMT s'avere developper une resistance acquise au vandetanib, par l'intermediaire de mecanismes essentiellement inconnus. Cette etude visait a examiner le role de YAP (Yes-Associated Protein) dans la resistance du CMT au vandetanib. Des cellules TT ont ete traitees au vandetanib pendant trois mois afin de generer des cellules qui lui sont resistantes (TT-R). Les auteurs ont etudie le role de YAP dans la resistance au vandetanib des cellules TT-R en realisant des mesures de proliferation et de formation de colonies, et examine les effets antitumoraux d'un inhibiteur de YAP et du vandetanib dans un modele de xenogreffes chez la souris. La CI50 du vandetanib etait 6-fois plus elevee envers les cellules TT-R comparativement aux cellules TT. La surexpression de YAP donnait lieu a une resistance au vandetanib alors que le knockdown de YAP retablissait la sensibilite des cellules TT-R au vandetanib. L'inhibiteur de YAP agissait en synergie avec le vandetanib sur les cellules tumorales. Ces resultats suggerent que YAP joue un role important dans la resistance acquise des cellules de CMT au vandetanib, jetant les bases d'une strategie de lutte contre le CMT a partir d'inhibiteurs de YAP et du vandetanib. [Traduit par la Redaction] Mots-cles : cancer medullaire de la thyroide, YAP, vandetanib, resistance., Introduction Thyroid cancers are classified into 4 subgroups, based on the cell types. The types include papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), medullary thyroid cancer (MTC), and anaplastic [...]

Background While the role of BRCA1/2 genes in familial breast and ovarian cancer is well established, their implication in the sporadic form of both cancers is still controversial. With the development of poly (ADP-ribose) polymerase (PARP) inhibitors, the exact relationship between BRCA1/2 genes and sporadic triple negative breast cancer/high grade serous carcinoma (TNBC/HGSC) needs to be further investigated. Therefore, we conducted a study in which we analyze BRCA1/2 point mutations and copy number alterations in Moroccan patients suffering from TNBC/HGSC. Methods To achieve our goal, we analyzed BRCA1/2 genes in the FFPE tissue blocks and blood samples of 65 TNBC/HGSC selected patients, using next generation sequencing technology. Results From the 65 successfully sequenced patients in our cohort, we detected five-point variants in six different patients, four variants were classified as pathogenic and one of unknown significance. Regarding copy number alterations we detected one copy number loss in BRCA1 gene and one copy number gain in BRCA2 gene. The genetic screening of BRCA1/2 genes using these patients' genomic DNA indicated that five harbored a germline genetic alteration. While three harbored a somatic genetic alteration. To the best of our knowledge, three-point variants detected in our study have never been reported before. Conclusion According to the results found in the present study, in a population without a family history of cancer, the possibility of a BRCA1/2 somatic pathogenic variant in high grade serous carcinoma is 7%. While for Triple negative breast cancer somatic point variants and copy number alterations seems to be a very rare genetic event. Keywords: Triple negative breast cancer, High grade serous ovarian Cancer, BRCA1/2, Morocco, Author(s): Fatima Zahra El Ansari[sup.1,2], Farah Jouali[sup.2], Rim Fekkak[sup.2], Joaira Bakkach[sup.1], Naima Ghailani Nourouti[sup.1], Amina Barakat[sup.1], Mohcine Bennani Mechita[sup.1] and Jamal Fekkak[sup.2] Background BRCA1 and BRCA2 genes encode for tumor [...]

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations.sup.1-7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling--including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice.sup.8-11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis. Whole-exome sequencing of colon organoids derived from patients with ulcerative colitis identifies somatic mutations in components of the IL-17 signalling pathway, which may confer a growth advantage to cells under inflammatory conditions., Author(s): Kosaku Nanki [sup.1] [sup.2] , Masayuki Fujii [sup.1] [sup.3] , Mariko Shimokawa [sup.1] , Mami Matano [sup.1] , Shingo Nishikori [sup.1] [sup.4] , Shoichi Date [sup.1] [sup.4] , Ai [...]

After three decades of false starts, gene therapy against the disease is in new clinical trials -- and there is even hope of a cure. After three decades of false starts, gene therapy against the disease is in new clinical trials -- and there is even hope of a cure., Author(s): Roxanne Khamsi Author Affiliations: Gene therapy could offer an inclusive cure for cystic fibrosis Henry Brady was diagnosed with cystic fibrosis at three weeks of age. Credit: Courtesy of [...]

New combinations of molecules put many patients on the path to good health. But those with rarer mutations are, for now, left behind. New combinations of molecules put many patients on the path to good health. But those with rarer mutations are, for now, left behind., Author(s): Sarah DeWeerdt Author Affiliations: Cystic fibrosis drugs target the malformed proteins at the root of the disease Credit: Russell Cobb Illustration of mechanics working inside a pair of lungs [...]

Background The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited. Methods We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing. Results Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS. Conclusions TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations. Keywords: TP53 mutation, Breast cancer, Li-Fraumeni syndrome, Lifetime risk, Author(s): Abdul Khalid Siraj[sup.1], Tariq Masoodi[sup.1], Rong Bu[sup.1], Sandeep Kumar Parvathareddy[sup.1], Kaleem Iqbal[sup.1], Saud Azam[sup.1], Maha Al-Rasheed[sup.1], Dahish Ajarim[sup.2], Asma Tulbah[sup.3], Fouad Al-Dayel[sup.3] and Khawla Sami Al-Kuraya[sup.1,4] Background TP53 (RefSeq [...]