Variants of Human Mucin Genes in Clear Cell Renal Cell Carcinoma and their Potential Prognostic and Predictive Values.

BACKGROUND: There is no reliable prognostic and predictive biomarkers for clear cell renal cell carcinoma (cc-RCC). METHODS: DNA from 47 cc-RCC tissue samples were sequenced using next generation sequencing and a customized gene panel testing for tumor-driver genes including 19 Mucin genes. RESULTS: Distinctive variants in 12 Mucin genes were present in all samples. These genes are: MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC12, MUC16, MUC17, MUC19, and MUC22. The numbers of distinctive and non-distinctive variants were counted for each sample. The median number of variants was 455. High variant number (HVN) (>455) was associated with shorter overall survival compared to low variant number (≤455) [Median 50 months vs. not reached; P=0.041]. In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival. CONCLUSION: Alterations in Mucin family genes are common in ccRCC. HVN is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs. KEY WORDS: Mucin; Variants; Renal cell carcinoma; Biomarker; Tyrosine kinase inhibitors.

CACSV: a computational web-sever that provides classification for cancer somatic genetic variants from different tissues.

BACKGROUND: Understanding the role and function of genetic variants is extremely important when analyzing and interpreting a myriad of human disease processes. For cancer in general, cell-specific genetic variants are ubiquitous and distinct tissues have significantly heterogenic genetic profiles. In clinical practice, only a few genetic variants have identifiable clinical utility. Finding clinically relevant genetic variants constitute a challenging process. In addition, there had been no reference protocol to provide guidance for cancer somatic genetic variants classification and interpretation. In 2017, the first version of a reference protocol was published by the Association for Molecular Pathology, the American Society of Clinical Oncology, and the College of American Pathologists. Previously, we incorporated the reference protocol into a computational method to expedite the process of identification of clinically relevant genetic variants. In this work, we developed a computational web-server to increase the accessibility and availability of clinically relevant genetic variants. RESULTS: Our work provides the clinical classification for ~ 3 million cancer genetic variants that are now publicly available in a shareable database on GitHub. We have developed a graphical user interface for the database to enhance the accessibility and ease-of-use. CONCLUSION: CACSV provides an open-source for about 3 million cancer tissue-specific genetic variants with their assigned clinical annotations.

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants.

BACKGROUND & OBJECTIVE: Genomic medicine stands to be revolutionized by understanding single nucleotide variants (SNVs) and their expression in single-gene disorders (Mendelian diseases). Computational tools can play a vital role in the exploration of such variations and their pathogenicity. Consequently, we developed the ensemble prediction tool AllelePred to identify deleterious SNVs and disease causative genes. RESULTS: The model utilizes different population genetics backgrounds and restricted criteria for features selection to help generate high accuracy results. In comparison to other tools, such as Eigen, PROVEAN, and fathmm-MKL our classifier achieves higher accuracy (98%), precision (96%), F1 score (93%), and coverage (100%) for different types of coding variants. The new method was also compared against a bioinformatics analytical workflow, which uses gnomAD overall AFs (less than 1%) and CADD (scaled C-score of at least 15). Furthermore, this research highlights the stature of genetic variant sharing and curation. We accumulated a list of highly probable deleterious variants and recommended further experimental validation before medical diagnostic usage. CONCLUSIONS: The ensemble prediction tool AllelePred enables increased accuracy in recognizing deleterious SNVs and the genetic determinants in real clinical data.

Clinically actionable cancer somatic variants (CACSV): a tumor interpreted dataset for analytical workflows.

BACKGROUND: The recent development and enormous application of parallel sequencing technology in oncology has produced immense amounts of cell-specific genetic information. However, publicly available cell-specific genetic variants are not explained by well-established guidelines. Additionally, cell-specific variants interpretation and classification has remained a challenging task and lacks standardization. The Association for Molecular Pathology (AMP), the American Society of Clinical Oncology (ASCO), and the College of American Pathologists (CAP) published the first consensus guidelines for cell-specific variants cataloging and clinical annotations. METHODS: AMP-ASCO-CAP recommended sources and information were downloaded and used as follows: relative knowledge in oncology clinical practice guidelines; approved, investigative or preclinical drugs; supporting literature and each gene-tumor site correlation. All information was homogenized into a single knowledgebase. Finally, we incorporated the consensus recommendations into a new computational method. RESULTS: A subset of cancer genetic variants was manually curated to benchmark our method and well-known computational algorithms. We applied the new method on freely available tumor-specific databases to produce a clinically actionable cancer somatic variants (CACSV) dataset in an easy-to-integrate format for most clinical analytical workflows. The research also showed the current challenges and limitations of using different classification systems or computational methods. CONCLUSION: CACSV is a step toward cell-specific genetic variants standardized interpretation as it is readily adaptable by most clinical laboratory pipelines for somatic variants clinical annotations. CACSV is freely accessible at ( https://github.com/tsobahytm/CACSV/tree/main/dataset ).

Biweekly cetuximab in combination with capecitabine and oxaliplatin (XELOX) or irinotecan (XELIRI) in the first-line and second-line treatment of patients with RAS wild-type metastatic colorectal cancer.

Background: Oral capecitabine in combination with intravenous oxaliplatin (XELOX) or irinotecan (XELIRI) are acceptable substitutions to fully intravenous regimens. Biweekly (as opposed to weekly) cetuximab is more convenient when combined with biweekly chemotherapy. Here, we report the tolerability and efficacy of biweekly cetuximab in combination with biweekly XELOX or XELIRI in patients with RAS wild-type metastatic colorectal cancer (RAS-WT mCRC). Methods: Clinical data of consecutive patients with mCRC who received biweekly cetuximab (500 mg/m2) in combination with XELOX or XELIRI between January 2009 and May 2019 in the first- or second-line settings was extracted. Dosage of XEL (Capecitabine/XELODA) was 1,000 mg/m2 twice daily for 9 days, plus on day 1 oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. Treatment dose reduction and delay for ≥7 days was analysed as surrogates for toxicity. Extended RAS testing was performed in the context of this study for patients who received treatment based on limited KRAS-WT genotype. Results: Sixty one patients with RAS-WT mCRC fulfilled the eligibility criteria. XELOX was administered to 26 (42.6%) and XELIRI to 35 (57.4%) of patients. For all patients in the first-line setting, the objective response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were 54%, 8 months and 25 months, respectively. The corresponding outcomes for the subgroup of patients who received first-line XELOX were 68%, 10 months and not reached, respectively. For all patients in the second-line setting, the ORR, PFS and OS were 50%, 7 months and 20 months, respectively. Chemotherapy components dose reduction and delays were observed in 18 (29.5%) and 25 (41%) patients, respectively. The corresponding frequencies for cetuximab were 3 (5%) and 31 (50.8%). Conclusion: Biweekly cetuximab in combination with XELOX or XELIRI is tolerable and effective. The addition of cetuximab to capecitabine and oxaliplatin is associated with favourable outcome.

The role of BRCA1/2 in hereditary and familial breast and ovarian cancers.

BACKGROUND: BRCA1/2 pathogenic variants have become associated with familial breast and ovarian cancers, and hereditary cancer-predisposition syndrome. With advances in molecular biology, BRCA profiling facilitates early diagnosis and the implementation of preventive and therapeutic strategies. The genes exhibit variable prevalence among different individuals and moderate interpretation complexity. BRCA deficiency is instrumental in cancer development, affects therapeutic options and is instrumental in drug resistance. In addition, BRCA1/2 profile is diverse across different groups and has been associated with the "founder effect" in certain populations. METHODS: In this review, we aim to detail the spectrum of BRCA1/2 variants and their associated risk estimates. RESULTS: The relationship between BRCA1/2 and hereditary and familial cancers is indisputable, yet BRCA screening methods are beset with limitations and lack clinical confidence. CONCLUSION: This review emphasizes the importance of screening BRCA genetics, in addition to their clinical utility. Furthermore, founder variants are anticipated in the Saudi population.

Quantitative DNA analysis of very low-level hepatitis B viremic patients reporting to the gastroenterology clinic.

OBJECTIVE: To examine data on very low-level viremic hepatitis B virus (HBV) infections in patients reporting to a gastroenterology clinic, and to investigate methods to improve analysis to avoid missing follow-up data and improve the management of HBV infection, and minimize morbidity and mortality outcomes. METHODS: A total of 104 patients with very low-level viremic HBV whom reported to the gastroenterology clinic at Al-Hada Armed Forces Hospital, Taif, Saudi Arabia and had a reading of <12 IU/mL on the real time (RT) polymerase chain reaction (PCR) detection system were enrolled in this study. For serological testing (for example, hepatitis B surface antigen [HBsAg]), we examined patients' results recorded in the laboratory information system since early 2007. Liver enzymes, alanine aminotransferase, and aspartate aminotransferase were assessed in some cases. RESULTS: After analyzing the data collected from 1,178 patients, we found 104 (8.83%) cases that fit the criteria for our study, including a reading of <12 IU/mL. We formed 6 groups of participants based on HBsAg reactivity and very low, elevated, or no viremia, and found 4 cases of continuous occult hepatitis B infection. CONCLUSION: The very low levels of DNA found had a diagnostic impact on the management of HBI and yielded several suggestions for clinicians regarding follow-up with patients. It is important to use a sensitive RT PCR to monitor the course of HBV infection.