Analysis of 30 Putative BRCA1 Splicing Mutations in Hereditary Breast and Ovarian Cancer Families Identifies Exonic Splice Site Mutations That Escape In Silico Prediction

Cancer mortality data were obtained from the WHO Mortality Database. Lung cancer, with about 85% being non-small cell lung cancer is one of the most common malignant tumors, considered the leading cause of cancer-related death in both men and women (associated with breast and ovarian cancer in metastasis). From published data, we designed a preventive vaccine in Silico aimed to protect against breast and ovarian cancer involved in metastasis for lung cancer. The largest increases are expected for melanoma; cancers of the prostate, kidney, liver, and urinary bladder in males; and the lung, breast, uterus, ovarian, and thyroid in females. Among all women, lung cancer mortality rates have surpassed those for breast cancer around the world. This reflects the decline of breast cancer mortality due to screening access and effective treatment alongside entrance of certain countries lifestyle and behavior in which smoking has become more prevalent in women. One aim of this research paper is to provide a better understanding for the potential dormant repositories of outbreaks and potential metastasis of breast and ovarian cancer and its consequents in lung cancer. In this study, we present to the cDNA-peptide fusion a more stable anti-tumoral against breast and ovarian cancer. As a cDNA target, we used primers from Her2 gene fusion with peptides from Her2 and human PARP-1 proteins. Our analysis identified 16 cloning DNA (cDNA) with theorical fusion stability (FS) value among 49.30-62.41 range and theorical Exosome Affinity (EA) (cDNA-peptide and exosome) among 62.60-77.10 range. We proposed a cDNA-peptide with theorical fusion value stability FS=50.36 Cruz and exosome affinity EA=68.02 Ro. We have named the cDNA-peptide selection as: LCR_2020_B008-55. In addition, in Silico, this cDNA-peptide also manifests partial inhibiting activity on the methylated promoter genes in lung tumors, therefore, this chimera cDNA-peptide may achieve a higher representative antitumoral activity against lung cancer disease. According to the anti-tumoral monitoring after and before vaccination using the candidate LCR_2020_B008-55, we proposed exosomes as biomarkers of lung carcinogenesis after and before vaccination. Due to the cDNA-peptides, in Silico, manifesting high affinity with exosomes, where our proposed vaccine may reach high representative activity against breast, ovarian and lung cancer in a metastasis stage, we identified this chimera with a triple antitumoral action.

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Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening

Frontiers in Oncology ◽

10.3389/fonc.2020.568786 ◽

2021 ◽

Vol 10 ◽

Author(s):

Mohammed Shaad N. Kadri ◽

Komal M. Patel ◽

Poonam A. Bhargava ◽

Franky D. Shah ◽

Nutan V. Badgujar ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

In Silico ◽

Indian Population ◽

Brca2 Gene ◽

Breast And Ovarian Cancer ◽

Prediction Tools ◽

Ovarian Cancers ◽

Brca Genes ◽

Pathogenic Mutations

BackgroundBreast and ovarian cancers are the most prevalent cancers and one of the leading causes of death in Indian women. The healthcare burden of breast and ovarian cancers and the rise in mortality rate are worrying and stress the need for early detection and treatment.MethodsWe performed amplicon sequencing of 144 cases who had breast/ovarian cancer disease (total 137 cases are patients and seven are tested for BRCA1/2 carrier) Using our custom designed gene panel consisting of 14 genes, that are associated with high to moderate risk of breast and ovarian cancers. Variants were called using Torrent Variant Caller and were annotated using ThermoFisher’s Ion Reporter software. Classification of variants and their clinical significance were identified by searching the variants against ClinVar database.ResultsFrom a total of 144 cases, we were able to detect 42 pathogenic mutations in [40/144] cases. Majority of pathogenic mutations (30/41) were detected in BRCA1 gene, while (7/41) pathogenic mutations were detected in BRCA2 gene, whereas, (2/41) pathogenic mutations were detected in TP53 gene and BRIP1, PALB2, and ATM genes respectively. So, BRCA genes contributed 88.09% of pathogenic mutations, whereas non-BRCA genes contributed 11.91% of pathogenic mutations. We were also able to detect 25 VUS which were predicted to be damaging by in silico prediction tools.ConclusionEarly detection of cancers in the Indian population can be done by genetic screening using customized multi-gene panels. Indications of our findings show that in the Indian population, apart from the common BRCA genes, there are other genes that are also responsible for the disease. High frequency mutations detected in the study and variants of uncertain significance predicted to be damaging by in silico pathogenicity prediction tools can be potential biomarkers of hereditary breast and ovarian cancer in Indian HBOC patients.

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