Transforming Diagnosis and Therapeutics Using Cancer Genomics.

In past quarter of the century, much has been understood about the genetic variation and abnormal genes that activate cancer in humans. All the cancers somehow possess alterations in the DNA sequence of cancer cell's genome. In present, we are heading toward the era where it is possible to obtain complete genome of the cancer cells for their better diagnosis, categorization and to explore treatment options.

'Breast Cancer Resistance Likelihood and Personalized Treatment Through Integrated Multiomics'.

In recent times, enormous progress has been made in improving the diagnosis and therapeutic strategies for breast carcinoma, yet it remains the most prevalent cancer and second highest contributor to cancer-related deaths in women. Breast cancer (BC) affects one in eight females globally. In 2018 alone, 1.4 million cases were identified worldwide in postmenopausal women and 645,000 cases in premenopausal females, and this burden is constantly increasing. This shows that still a lot of efforts are required to discover therapeutic remedies for this disease. One of the major clinical complications associated with the treatment of breast carcinoma is the development of therapeutic resistance. Multidrug resistance (MDR) and consequent relapse on therapy are prevalent issues related to breast carcinoma; it is due to our incomplete understanding of the molecular mechanisms of breast carcinoma disease. Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. For management of breast carcinoma, the treatment decision not only depends on the assessment of prognosis factors but also on the evaluation of pathological and clinical factors. Integrated data assessments of these multiple factors of breast carcinoma through multiomics can provide significant insight and hope for making therapeutic decisions. This omics approach is particularly helpful since it identifies the biomarkers of disease progression and treatment progress by collective characterization and quantification of pools of biological molecules within and among the cancerous cells. The scrupulous understanding of cancer and its treatment at the molecular level led to the concept of a personalized approach, which is one of the most significant advancements in modern oncology. Likewise, there are certain genetic and non-genetic tests available for BC which can help in personalized therapy. Genetically inherited risks can be screened for personal predisposition to BC, and genetic changes or variations (mutations) can also be identified to decide on the best treatment. Ultimately, further understanding of BC at the molecular level (multiomics) will define more precise choices in personalized medicine. In this review, we have summarized therapeutic resistance associated with BC and the techniques used for its management.

Association of TNF-α polymorphisms (-857, -863 and -1031), TNF-α serum level and lipid profile with acne vulgaris.

BACKGROUND: Acne is an inflammatory condition principally affected by genetic and dietary factors. Investigation into functional polymorphisms of TNF-α gene and their association with acne vulgaris will be helpful in exploring genetic influence on skin immune mediated inflammatory events. In the present study, we analyzed association of TNF-α gene polymorphisms, its expression levels and lipid profiles in a large cohort of acne patients and controls. METHODS: We used PCR-RFLP to study association of TNF-α polymorphisms at -857C/T, -863C/A and -1031 T/C sites with acne vulgaris. Lipid profiles were measured using enzymatic end-point method. The serum levels of TNF-α and apolipoprotein a were measured using ELISA. NIH, LDlink was used to investigate patterns of linkage disequilibrium across south Asian reference genome (Punjabi from Lahore Pakistan). RESULTS: We found that TNF-α -863 polymorphism is strongly associated with acne in overall population as well as in gender and severity based groups of acne patients. Polymorphisms at -863 and -1031 position were in linkage disequilibrium. Importantly, TNF-α serum level was significantly increased in acne patients with severe disease symptoms. Furthermore, levels of total cholesterol (TC) and triglycerides (TG) were significantly increased, whereas high density lipoprotein cholesterol (HDL-C) level was significantly decreased in acne patients. The levels of apolipoprotein a varied widely in studied populations and no significant difference was found in the analyzed groups. CONCLUSION: In conclusion, we found that TNF-α expression increases in acne patients affected by TNF-α polymorphisms, and that the lipid profile is specifically disrupted in acne patients.

Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.

BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

Frameshift Sequence Variants in the Human Lipase-H Gene Causing Hypotrichosis.

Hypotrichosis is a condition of abnormal hair pattern characterized by sparse to absent hair on different parts of the body, including the scalp. The condition is often characterized by tightly curled woolly hairs, discoloration of hair, and development of multiple keratin filled cysts or papules on the body. Sequence analysis of the lipase H (LIPH) gene, mapped on chromosome 3q27.3, led to the identification of a novel frameshift deletion variant (c.932delC, p.Pro311Leufs*3) in one family and previously reported 2-bp deletion (c.659_660delTA) in five other families, inherited hypotrichosis, and woolly hair in an autosomal recessive pattern. The study further extends the body of evidence that sequence variants in the LIPH gene result in hypotrichosis and woolly hair phenotype.

Disease causing homozygous variants in the human hairless gene.

BACKGROUND: Atrichia with papular lesions (APL) is a rare irreversible form of complete hair loss inherited in autosomal recessive manner. Hair loss is often followed by the appearance of multiple keratin-filled cysts or papules on exterior parts of the body. This phenotype results due to mutations in the human hairless gene (HR) mapped on chromosome 8p21.3. The present study was aimed to search for disease-causing sequence variants in the HR gene in five consanguineous families exhibiting features of APL. METHODS: Linkage in five Pakistani lineal consanguineous families, displaying features of APL, was tested using microsatellite markers flanking the HR gene on chromosome 8p21.3. After constructing the haplotypes, variants in the gene HR were searched by dideoxy-chain termination sequencing. RESULTS: Haplotype analysis established linkage in all five families to the HR gene located on chromosome 8p.21.3. Subsequently, sequencing HR identified a novel homozygous nonsense variant (c.2541G>A, p.Trp847*) in one and previously reported two pathogenic variants (p.Cys690*, p.Pro1157Arg) in the other four families. CONCLUSION: Mutations identified extend the spectrum of mutations in the HR gene resulting in APL. Characterizing the clinical spectrum resulting from the disease-causing homozygous variants in the HR gene will direct clinical care of the family members.