Description of the genetic variants identified in a cohort of patients diagnosed with localized anal squamous cell carcinoma and treated with panitumumab

Càncer; Genètica mèdica; Marcadors predictiusCáncer; Genética Médica; Marcadores predictivosCancer; Medical genetics; Predictive markersSquamous cell carcinoma is the most frequent histologic type of anal carcinoma. The standard of care since the 1970s has been a combination of 5-fluorouracil, mitomycin C, and radiotherapy. This treatment is very effective in T1/T2 tumors (achieving complete regression in 80–90% of tumors). However, in T3/T4 tumors, the 3-year relapse free survival rate is only 50%. The VITAL trial aimed to assess the efficacy and safety of panitumumab in combination with this standard treatment. In this study, 27 paraffin-embedded samples from the VITAL trial and 18 samples from patients from daily clinical practice were analyzed by whole-exome sequencing and the influence of the presence of genetic variants in the response to panitumumab was studied. Having a moderate- or high-impact genetic variant in PIK3CA seemed to be related to the response to panitumumab. Furthermore, copy number variants in FGFR3, GRB2 and JAK1 were also related to the response to panitumumab. These genetic alterations have also been studied in the cohort of patients from daily clinical practice (not treated with panitumumab) and they did not have a predictive value. Therefore, in this study, a collection of genetic alterations related to the response with panitumumab was described. These results could be useful for patient stratification in new anti-EGFR clinical trials.LT-F is supported by the Spanish Economy and Competitiveness Ministry (DI-15-07614)

Genetic profile and functional proteomics of anal squamous cell carcinoma: proposal for a molecular classification

Carcinoma anal de cèl·lules escamoses; Biologia molecular; ProteòmicaAnal squamous cell carcinoma; Molecular biology; ProteomicsCarcinoma anal de células escamosas; Biología molecular; ProteómicaAnal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo. Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST. Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.This study was supported by the Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry, Spain and co-sponsored by the FEDER program, “Una forma de hacer Europa” (PI15/01310), a Roche Farma grant, Cátedra UAM-Amgen and a grant of Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD1403). LT-F is supported by the Spanish Economy and Competitiveness Ministry (DI-15–07614). GP-V is supported by the Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (IND2017/BMD7783); AZ-M is supported by Jesús Antolín Garciarena fellowship from IdiPAZ. The authors have declared a conflict of interest. JAFV and AG-P are shareholders in Biomedica Molecular Medicine SL. LT-F and GP-V are employees of Biomedica Molecular Medicine SL. JC has received honoraria for scientific consulting (as speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi and Merck Serono and research support from Eisai, Novartis, Ipsen, Astrazeneca, Pfizer and Advanced Accelerator Applications. IG has received honoraria and/or travel expenses from Roche, Sanofi, Merck, Servier, Amgen and Sirtflex, and for advisory role from Merck and Sanofi. JF has received consulting and advisory honoraria from Amgen, Ipsen, Eissai, Merck, Roche and Novartis; research funding from Merck, and travel and accommodation expenses from Amgen and Servier. The other authors declare no conflicts of interest

Comprehensive Characterization of the Mutational Landscape in Localized Anal Squamous Cell Carcinoma

Carcinoma anal de cèl·lules escamoses; Neoplàsia rara; PronòsticCarcinoma anal de células escamosas; Neoplasia rara; PronósticoAnal squamous cell carcinoma; Rare neoplasm; PrognosisAnal squamous cell carcinoma (ASCC) is a rare neoplasm. Chemoradiotherapy is the standard of care, with no therapeutic advances achieved over the past three decades. Thus, a deeper molecular characterization of this disease is still necessary. We analyzed 46 paraffin-embedded tumor samples from patients diagnosed with primary ASCC by exome sequencing. A bioinformatics approach focused in the identification of high-impact genetic variants, which may act as drivers of oncogenesis, was performed. The relation between genetics variants and prognosis was also studied. The list of high-impact genetic variants was unique for each patient. However, the pathways in which these genes are involved are well-known hallmarks of cancer, such as angiogenesis or immune pathways. Additionally, we determined that genetic variants in BRCA2 , ZNF750 , FAM208B , ZNF599 , and ZC3H13 genes are related with poor disease-free survival in ASCC. This may help to stratify the patient's prognosis and open new avenues for potential therapeutic intervention. In conclusion, sequencing of ASCC clinical samples appears an encouraging tool for the molecular portrait of this disease.This study was supported by Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry , Spain and co-funded by the FEDER program “Una forma de hacer Europa” ( PI15/01310 ), a Roche Farma funding, Amgen and a grant from Grupo Español Multidisciplinar en Cáncer Digestivo ( GEMCAD1403 ). L. T.-F. is supported by the Spanish Economy and Competitiveness Ministry ( DI-15-07614 ). G. P.-V. and E. L.-C. are supported by the Consejería de Educación, Juventud y Deporte of Comunidad de Madrid ( IND2017/BMD7783 ); A. Z.-M. is supported by a Jesús Antolín Garciarena fellowship from IdiPAZ . The funders played no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Proteomics suggests a role for APC-survivin in response to somatostatin analog treatment of neuroendocrine tumors

CONTEXT: Somatostatin analogs are established in the treatment of neuroendocrine tumors (NETs) including small intestinal NET; however, the molecular mechanisms are not well known. Here, we examined the direct effects of lanreotide in NET cell line models. SETTING AND DESIGN: The cell lines HC45 and H727 were treated with 10nM lanreotide for different time periods and alterations of the proteome were analyzed by in-depth high-resolution isoelectric focusing tandem liquid chromatography-mass spectrometry. We next investigated whether the observed suppression of survivin was mediated by adenomatous polyposis coli (APC) and possible effects on tumor proliferation in vitro. Expression of survivin was assessed by immunohistochemistry in 112 NET cases and compared with patient outcome. RESULTS: We quantified 6451 and 7801 proteins in HC45 and H727, respectively. After short time lanreotide treatment APC was increased and survivin reduced. Overexpression of APC in H727 cells decreased, and APC knock-down elevated the survivin level. The lanreotide regulation of APC-survivin could be suppressed by small interfering RNA against somatostatin receptor 2. Although lanreotide only gave slight inhibition of proliferation, targeting of survivin with the small molecule YM155 dramatically reduced proliferation. Moderate or high as compared with low or absent total survivin expression was associated with shorter progression-free survival, independent of tumor stage, grade, and localization. CONCLUSIONS: We report a proteome-wide analysis of changes in response to lanreotide in NET cell lines. This analysis suggests a connection between somatostatin analog, APC, and survivin levels. Survivin is a possible prognostic factor and a new potential therapeutic target in NETs

Description of the genetic variants identified in a cohort of patients diagnosed with localized anal squamous cell carcinoma and treated with panitumumab

Squamous cell carcinoma is the most frequent histologic type of anal carcinoma. The standard of care since the 1970s has been a combination of 5-fluorouracil, mitomycin C, and radiotherapy. This treatment is very effective in T1/T2 tumors (achieving complete regression in 80-90% of tumors). However, in T3/T4 tumors, the 3-year relapse free survival rate is only 50%. The VITAL trial aimed to assess the efficacy and safety of panitumumab in combination with this standard treatment. In this study, 27 paraffin-embedded samples from the VITAL trial and 18 samples from patients from daily clinical practice were analyzed by whole-exome sequencing and the influence of the presence of genetic variants in the response to panitumumab was studied. Having a moderate- or high-impact genetic variant in PIK3CA seemed to be related to the response to panitumumab. Furthermore, copy number variants in FGFR3, GRB2 and JAK1 were also related to the response to panitumumab. These genetic alterations have also been studied in the cohort of patients from daily clinical practice (not treated with panitumumab) and they did not have a predictive value. Therefore, in this study, a collection of genetic alterations related to the response with panitumumab was described. These results could be useful for patient stratification in new anti-EGFR clinical trial

Comprehensive Characterization of the Mutational Landscape in Localized Anal Squamous Cell Carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare neoplasm. Chemoradiotherapy is the standard of care, with no therapeutic advances achieved over the past three decades. Thus, a deeper molecular characterization of this disease is still necessary. We analyzed 46 paraffin-embedded tumor samples from patients diagnosed with primary ASCC by exome sequencing. A bioinformatics approach focused in the identification of high-impact genetic variants, which may act as drivers of oncogenesis, was performed. The relation between genetics variants and prognosis was also studied. The list of high-impact genetic variants was unique for each patient. However, the pathways in which these genes are involved are well-known hallmarks of cancer, such as angiogenesis or immune pathways. Additionally, we determined that genetic variants in BRCA2, ZNF750, FAM208B, ZNF599, and ZC3H13 genes are related with poor disease-free survival in ASCC. This may help to stratify the patient's prognosis and open new avenues for potential therapeutic intervention. In conclusion, sequencing of ASCC clinical samples appears an encouraging tool for the molecular portrait of this disease.This study was supported by Instituto de Salud Carlos III, Spanish Economy and CompetitivenessMinistry, Spain and co-funded by the FEDER program "Una forma de hacer Europa" (PI15/01310), a Roche Farma funding, Amgen and a grant from Grupo Espanol Multidisciplinar en Cancer Digestivo (GEMCAD1403). L. T.-F. is supported by the Spanish Economy and Competitiveness Ministry (DI-15-07614). G. P.-V. and E. L.-C. are supported by the Consejeria de Educacion, Juventud y Deporte of Comunidad de Madrid (IND2017/BMD7783); A. Z.-M. is supported by a Jesus Antolin Garciarena fellowship from IdiPAZ. The funders played no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.S

Comprehensive Characterization of the Mutational Landscape in Localized Anal Squamous Cell Carcinoma

Anal squamous cell carcinoma (ASCC) is a rare neoplasm. Chemoradiotherapy is the standard of care, with no therapeutic advances achieved over the past three decades. Thus, a deeper molecular characterization of this disease is still necessary. We analyzed 46 paraffin-embedded tumor samples from patients diagnosed with primary ASCC by exome sequencing. A bioinformatics approach focused in the identification of high-impact genetic variants, which may act as drivers of oncogenesis, was performed. The relation between genetics variants and prognosis was also studied. The list of high-impact genetic variants was unique for each patient. However, the pathways in which these genes are involved are well-known hallmarks of cancer, such as angiogenesis or immune pathways. Additionally, we determined that genetic variants in BRCA2, ZNF750, FAM208B, ZNF599, and ZC3H13 genes are related with poor disease-free survival in ASCC. This may help to stratify the patient's prognosis and open new avenues for potential therapeutic intervention. In conclusion, sequencing of ASCC clinical samples appears an encouraging tool for the molecular portrait of this disease

Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide