Breast cancer molecular alteration

Molecular alterations The most frequently mutated and/or amplified genes in the tumour cells are TP53 (41% of tumours), PIK3CA (30%), MYC (20%), PTEN (16%), CCND1 (16%), ERBB2 (13%), FGFR1 (11%) and GATA3 (10%), as reported in a series of early breast cancers. These genes encode cell-cycle modulators that are either repressed (for example, p53) or activated (for example, cyclin D1), sustaining proliferation and/or inhibiting apoptosis, inhibiting oncogenic pathways that are activated (MYC, HER2 and FGFR1) or inhibiting elements that are no longer repressed (PTEN).

The majority of the mutations affecting 100 putative breast cancer drivers are extremely rare, therefore, most breast cancers are caused by multiple, low-penetrant mutations that act cumulatively. Luminal A tumours have a high prevalence of PIK3CA mutations (49%), whereas a high prevalence of TP53 mutations is a hallmark of basal-like tumours (84%).

For TNBC, different molecular drivers under- line its subtypes. At the metastatic stage, specific predictive alterations, such as PIK3CA mutations, can be easily detected non-invasively in the plasma in circulat- ing tumour DNA rather than on tumour biopsy; never- theless, depending on the technology used, the level of sensitivity may vary. 

Epigenetic alterations are involved in breast carcinogenesis and progression. In breast cancer, genes can be either globally hypomethylated (leading to gene activation, upregulation of oncogenes and chromosomal instability) or, less frequently, focally (locus-specific) hypermethylated (leading to gene repression and genetic instability due to the silencing of DNA repair genes).

Other epigenetic mechanisms involve histone tail modifications by DNA methylation, inducing chromatin structure changes to silence gene expression and nucleosomal remodelling. These changes are reversible, enzyme-mediated and potentially targetable. For example, in luminal-like breast cancer cell lines, inhibition of histone deacetylase with specific inhibitors such as vorinostat or chidamide can reverse resistance to endocrine therapy via inhibition of the resistance pathway driven by epidermal growth factor receptor signalling.

Recently, a phase III trial in metastatic luminal breast cancer showed the superiority of a treatment combining chidamide with endocrine therapy (namely, the aromatase inhibitor exemestane) to exemestane alone.

Immune crosstalk in breast cancer

Immune crosstalk in breast cancer. The immune reaction to breast cancer is initiated by the neoantigens expressed by tumour cells, encoded by altered genes and presented by antigen-presenting cells (APCs) on major histocompatibility complex class I (MHC I) or MHC II molecules. Neoantigen presentation results in activation of CD8+ (cytotoxic) and CD4+ (helper) T cells. CD8+ T cells are the main effector cell of the anti-tumour immune response; their activation (principally through the T cell receptor (TCR)) results in release of the cytolytic molecules perforin and granzyme B, which directly induce tumour cell lysis.

The anti-tumour action of CD8+ T cells is amplified by cytokines secreted from CD4+ T cells, namely IFNγ, IL-2 and tumour necrosis factor (TNF). Activated CD8+ T cells also upregulate expression of Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL; also known as TNFSF10) on their membrane, which induce apoptotic pathways to kill tumour cells.

Cancer cells elicit an innate immune response, comprising natural killer (NK) and NK T cells that are capable of direct tumour cell killing. Malignant cells can suppress the immune response by expressing immune checkpoint regulators (for example, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 ligand 1 (PD-L1)), which are upregulated by effector T cells as a consequence of chronic exposure to tumour antigens (T cell exhaustion).

The reduced anti-tumour immune response by upregulated immune checkpoint molecules establishes a pro-tumour microenvironment, which is further enriched by recruitment of immunosuppressive cells, T regulatory (Treg) cells and myeloid-derived stromal cells (MDSCs). Treg cells, which inhibit activation of CD4+ and CD8+ T cells, are induced by tumour-associated macrophages (TAMs) and by tumour-secreted and cancer-associated fibroblast (CAF)-secreted factors, such as transforming growth factor-β (TGFβ).

 In addition, TAMs and Treg cells inhibit APCs via IL-10 secretion, inducing a tolerogenic state of APCs. MDSCs are recruited to the tumour bed by tumour-secreted factors, inhibit trafficking of T cells to the tumour bed and inhibit effector T cell activation by upregulating 2,3-indoleamine- dioxygenase (IDO) and arginase expression, enzymes involved in the T cell nutrient depletion.

The secretome of the pro-tumour microenvironment, containing factors that stimulate angiogenesis and invasion (such as vascular-endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs)) also contribute to tumour immune escape and propagation. CCL22, CC-chemokine ligand 22; CXCL16, CXC-chemokine ligand 16; NOS, nitric oxide synthase; PD-1, programmed cell death 1; RANKL, receptor activator of nuclear factor-κB (RANK) ligand; TH1 cell, type 1 T helper cell. Adapted from ref. 75, CC-BY-4.0 https://creativecommons.org/licenses/by/4.0/

Causes and symptoms of cholesterol

Causes of Cholesterol

 If the cholesterol level in the blood exceeds the normal level, then this condition is known as hypercholesterolemia or high cholesterol. High cholesterol conditions can increase the risk of serious diseases. Cholesterol itself is a waxy fat compound which is mostly produced in the liver and some of it is obtained from food. Generally, heart attack and stroke are diseases that lurk with high cholesterol, which is caused by excessive cholesterol deposition in blood vessels. 

 Based on a report from WHO in 2011, about 35 percent of Indonesia's population is estimated to have cholesterol levels higher than the normal limit for health. This shows that one third of Indonesia's population is at high risk of arterial disease.

Eating foods with high cholesterol content or lack of exercise can also cause excess cholesterol, however, heredity can also be a trigger for cholesterol.

Cholesterol Symptoms

When there is deposition on artery walls due to excessive cholesterol levels, obstruction to blood flow to the heart, brain and other parts of the body can occur. High cholesterol increases a person's risk of narrowing the arteries or atherosclerosis, blood clots in certain parts of the body, minor strokes, strokes, and heart attacks.

Pain in the front of the chest or in the arms (angina) when a person is under stress or is doing strenuous physical activity can also be caused by high cholesterol. High cholesterol also increases a person's risk for coronary heart disease.

If you don't change your diet and don't stop smoking, people with high cholesterol will have an increased risk of having a stroke or heart disease. In cigarettes, a chemical called acrolein is found. This substance can stop the activity of good cholesterol or HDL to transport fat deposits to the liver. As a result, there can be narrowing of the arteries or atherosclerosis.

Effect of alcohol on liver health

Effect of Alcohol on Liver Health Alcohol has a significant impact on liver health. The liver has a fairly important role in the body, which regulates the metabolism of sugar, detoxifies the body, and helps relieve infection.

Also Read: Why Alcohol Reduces Chances of Pregnancy

If there is damage, the liver or liver can regenerate itself. Even so, an unhealthy lifestyle such as consuming alcoholic beverages interferes with this regeneration ability. If not treated immediately, the liver will suffer serious damage. One of the liver diseases caused by alcohol consumption is alcoholic fatty liver.

When it enters the body, alcohol travels to the bloodstream to the liver so as not to cause serious harm to other organs in the body. When digesting this alcohol, some of the liver cells are damaged and die. If you constantly consume alcohol, the liver can no longer do its job, in this case, it is digesting fat. As a result, fat will accumulate and there will be fatty liver.

The study, uploaded in the US National Library of Medicine, National Institutes of Health, states that the maximum limit of alcohol consumption associated with fatty liver disease in men is more than 80 grams and 40 grams for women per day.

If this habit is not stopped, the stage of fatty liver disease will increase to alcoholic hepatitis and cirrhosis as the most acute stage of alcohol-induced liver dysfunction.

Symptoms that arise in the body affected by fatty liver include swelling in the legs and abdomen, drastic weight loss, yellowing of the eyes and skin, chills fever, and vomiting of blood. In the chronic stage, the person experiences a coma and leads to death. This is why you are not allowed to consume excessive amounts of alcohol.

Recommendations on breast cancer population screening

 Recommendations on population screening

Population mammography screening recommendations (for women with average risk)  differ between countries and agencies, reflecting persistent non-consensus on the  magnitude of benefit (mortality reduction) and harms (in particular, the extent of  overdiagnosis), and how these outcomes balance out overall and in specific age groups.  

This is exemplified in selected recommendations:

• The US Preventive Services Task Force recommends screening every 2 years for women aged 50–74 years, and emphasizes individualized decisions for those aged 40–49 years that take account of the woman’s values

• Canadian guidelines support shared decisions, do not recommend screening for women aged 40–49 years and recommend screening every 2–3 years for women aged 50–69 years

• The American Cancer Society recommends annual screening for women aged 40–54 years, and a transition to 2-yearly screening for those aged ≥55 years (with the opportunity to continue annual screening)

• The International Agency for Research on Cancer reports that there is sufficient evidence that screening confers benefit in women aged 50–74 years (but limited evidence in the 40–49 years age group) and that there is sufficient evidence that mammography detects breast cancers that would never have been diagnosed or would never have caused harm if women had not been screened (overdiagnosis)

• European recommendations specify mammography through organized screening  programmes every 2–3 years in women aged 45–74 years (and suggest against annual screening)

Women at average risk do not have a pre-existing breast cancer or a previous diagnosis of a high-risk breast lesion (such as atypical ductal hyperplasia), and do not harbour arisk-enhancing genetic mutation (such as BRCA1 or BRCA2 mutations or other familial breast cancer syndromes).

Trple-negative breast cancer molecular classification

Triple-negative breast cancer molecular classification, Gene expression assays have identified six different triple-negative breast cancer (TNBC) molecular subtypes (Lehman’s classification).

These are

• basal-like 1 (BL1), 
• basal-like 2 (BL2), 
• mesenchymal-like (M),
• mesenchymal/stem-like (MSL),
• immunomodulatory (IM),
• and luminal androgen receptor (LAR).

BL1 has a high TP53 mutation rate (92%), alterations in genes involved in DNA repair mechanisms (such as BRCA1, BRCA2, TP53 and RB1) and a cell-cycle gene signature.

BL2 has cell-cycle gene signatures, overexpression of growth factor signalling genes and overexpression of myoepithelial differentiation genes.

M and MSL subtypes are enriched for genes encoding regulators of cell motility, invasion and mesenchymal differentiation, but the MSL subtype is uniquely enriched for the genes that encode regulators of epithelial–mesenchymal transition and stemness.

The Claudin-low subtype from the intrinsic classification is mostly composed of the M and MSL subtypes312. MSL also shares numerous genes involved in the regulation of immune response with the IM subtype.

Finally, LAR is characterized by a higher mutational burden with overexpression of genes coding for mammary luminal differentiation, overexpression of the regulators of the androgen receptor (AR) signalling pathway and increased mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes.

This classification has been refined into four groups: 

1. BL1 (immunoactivated),
2. BL2 (immunosuppressed),
3. M (including most of the MSL),
4. and LAR, with implications for response to neoadjuvant chemotherapy.

Combining RNA and DNA profiling analyses, a similar classification of TNBC has been reported (Burstein’s classification), divided into four distinct subtypes.

These subtypes are: 

• LAR,
• mesenchymal (MES),
• basal-like immunosuppressed (BLIS),
• and basal-like immune-activated (BLIA).

Each subtype has specific therapeutic targets (for example, the LAR subtype can be targeted via the AR and the cell surface protein mucin) and different prognosis (for example, the BLIA subtype is associated with better prognosis than BLIS). Despite these multiple efforts, there is no established diagnostic assay yet for the classification of TNBC in routine practice.

Breast cancer diagnostic work-ip

Women experiencing breast symptoms or breast changes, such as a lump, localized pain, nipple symptoms or skin changes, require appropriate diagnostic evaluation, as do women who are recalled for further testing because of positive screening mammography.

Diagnosing breast cancer is based on a triple test comprising clinical examination, imaging (usually mammography and/or ultrasonography) and needle biopsy. Assessment entails performing the appropriate elements of the triple test, factoring in the patients’ characteristics and presentation, and should be performed before beginning treatment.

Appropriate assessment helps to accurately discriminate between those who have breast cancer and those who have benign conditions (such as fibroadenoma) or normal breast changes and can be reassured or safely managed with follow-up, obviating the need for surgical intervention.

Ultrasonography is almost universally used to assess localized symptoms, as an initial imaging modality in young women, to identify and characterize screen- detected abnormalities and, preferentially, for imaging- guided percutaneous biopsy. Breast ultrasonography may also be used to characterize and biopsy axillary lymph nodes in women suspected of having breast cancer.

Imaging evaluation also includes MRI for specific clinical indications, such as in women for whom conventional imaging tests have been equivocal, inconclusive or discordant, for evaluating women with breast implants and for evaluating women with axillary nodal metastases but no detectable (occult) breast tumour.

Preoperative MRI is also selectively used for staging newly diagnosed disease, but this is a debated practice given the limited evidence on whether it enhances a patient’s clinical outcomes. However, MRI is advised for preoperative assessment of newly diagnosed invasive lobular cancers.