Global burden of breast cancer is expected to increase to >2 million new cases every year by 2030 and 10% of these are likely to have hereditary breast and ovarian cancer syndrome. Identifying these individuals by pedigree and BRCA1/2 mutation analyses will enable us to offer targeted mutation testing and appropriate counseling. This study from a tertiary care hospital showed that of the 127 breast cancer patients on treatment during 2014-2015, 24 of them fulfilled the criteria of hereditary breast and ovarian cancer syndrome after detailed verbal autopsy and pedigree analysis, and BRCA1 and 2 next-generation sequencing done after pre-test counseling revealed mutations in 13 cases (54%), these included 9 BRCA1 mutations (69%) and 4 BRCA2 mutation (31%). Subsequent post-test counseling recommended targeted mutation analysis for 64 high-risk members in these 13 families with pathogenic mutations, which will help in surveillance for early detection, appropriate management, and prevention of the disease by decreasing the burden to both family and nation. Results from this preliminary study highlight the importance of genetic counseling, pedigree analysis, and genetic testing. It can be recommended that all oncology units should have a genetic counseling service for providing appropriate support to oncologists, patients, and families to prevent unnecessary testing; however, breast cancer screening program is incomplete without evaluating for hereditary breast and ovarian cancer syndrome.
Infection-induced acute encephalopathies (IIAEs) are a group of neurologic disorders caused post infection. They are of 8 types, 6 of which are herpes specific, whereas IIAE3 and IIAE4 can be triggered by infections additional to herpeslike influenza, enterovirus, etc. IIAE3 is also known as acute necrotizing encephalopathy type 1, which is a rare type of encephalopathy that occurs following an infection in infancy or early childhood. Symptoms include fever, cough, congestion, vomiting, and diarrhea followed by seizures, hallucination, ataxia, and abnormal muscle tone, and sometimes it leads to untimely death. Here, we describe a familial case where 3 siblings were clinically diagnosed with acute necrotizing encephalopathy 1. Genetic testing revealed 2 heterozygous variations: RANBP2 c.5249C>G, p.P1750 R, and CPT2 c.365C>T, p.S122F. Variants in RANBP2 and CPT2 have been individually known to be associated with IIAE3 and IIAE4, respectively. Segregation analysis revealed that the RANBP2 variant was inherited from the father and the CPT2 variant from the mother. This case qualifies to be the first of its kind where digenic inheritance (ie, DNA sequence variants in 2 genes are required for the pathogenic phenotypes) appears to cause a lethal class of acute necrotizing encephalopathy.
Fibroadenoma is the most common type of benign breast tumor, accounting for 90% of benign lesions in India. Somatic mutations in the mediator complex subunit 12 (MED12) gene play a critical role in fibroepithelial tumorigenesis. The current study evaluated the hotspot region encompassing exon 2 of the MED12 gene, in benign and malignant breast tumor tissue from women who presented for breast lump evaluation. A total of 100 (80 fibroadenoma and 20 breast cancer) samples were analyzed by polymerase chain reaction-Sanger sequencing. Sequence variant analysis showed that 68.75% of nucleotide changes were found in exon 2 and the remaining in the adjacent intron 1. Codon 44 was implicated as a hotspot mutation in benign tumors, and 86.36% of the identified mutations involved this codon. An in silico functional analysis of missense mutations using consensus scoring sorting intolerant from tolerant (SIFT), SIFT seq, Polyphen2, Mutation Assessor, SIFT transFIC, Polyphen2 transFIC, Mutation Assesor transFIC, I-Mutant, DUET, PON-PS, SNAP2, and protein variation effect analyzer] revealed that apart from variants involving codon 44 (G44S; G44H), others like V41A and E55D were also predicted to be deleterious. Most of the missense mutations appeared in the loop region of the MED12 protein, which is expected to affect its functional interaction with cyclin C-CDK8/CDK19, causing loss of mediator-associated cyclin depended kinase (CDK) activity. These results suggest a key role of MED12 somatic variations in the pathogenesis of fibroadenoma. For the first time, it was demonstrated that MED12 sequence variations are present in benign breast tumors in the south Indian population.
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