Introduction 

Genetics can influence several aspects of one’s health. It can affect your risk of developing lymphoma, too. Some inherited conditions are linked to higher cancer risk, and they can influence the rate of cell growth and the response of the immune system to fight the disease. Inherited genetic mutations contribute to 5-10% of all cancers, including lymphoma.

What is MALT lymphoma?

MALT denotes mucosa-associated lymphoid tissue. MALT lymphoma is a form of B-cell non-Hodgkin lymphoma (NHL). It begins in the mucosa, which lines the interior of some organs, including the stomach. It arises due to the uncontrolled growth of lymphocytes (white blood cells). T-lymphocytes and B-lymphocytes are the two types present in our body. These function to fight infections and are circulated through the blood and lymphatic system, which is made up of tubes spread across different parts of the body called lymphatic vessels. MALT lymphoma does not occur in the lymph nodes; it develops in the body organs. Therefore, it is also called extranodal marginal zone lymphoma. Extranodal implies outside the lymph nodes. It should be noted that MALT lymphoma is not infectious.¹

Why does this topic matter?

About 7% of all NHLs are MALT lymphomas. In most cases, they develop in the stomach and are known as gastric MALT. They are also formed in skin, soft tissues, thyroid, lungs and salivary glands; categorised as non-gastric MALT. The symptoms differ according to the site of the disease.  In case of the stomach, abdominal pain, indigestion, loss of appetite, and nausea may occur. If it is developed in the lungs, persistent cough and breathlessness are observed. Symptoms such as drenching night sweats, high temperatures, and weight loss are identified as B symptoms. Individuals aged 65 and above are more likely to develop MALT lymphoma. It is more common in people assigned male at birth, and family history is a major risk factor.²

Purpose of this article

One of the main characteristics of MALT lymphomas is changes in DNA, which affect the molecular pathways. A spectrum of genetic aberrations exists, depending on the site of MALT lymphoma, summarised in Table 1. Having knowledge about genetic and molecular alterations that contribute to the disease development can help in creating awareness and assist in a personalised approach towards treatment methods.  

What causes MALT lymphoma? 

Long-term infections and inflammation

Areas of the body having long-term inflammation due to an infection are most likely to develop MALT lymphoma. Most often, MALT lymphomas in the stomach are caused by the bacteria Helicobacter pylori (H. pylori). An untreated infection can cause long-term inflammation of the stomach lining, which may trigger abnormal growth and transformation of B-lymphocytes into malignant cells, leading to MALT lymphoma over time. Chronic infections with Campylobacter jejuni in the small intestine, Borrelia burgdorferi in the skin, and Chlamydia psittaci in the ocular adnexa are other examples that can trigger MALT lymphoma. Hepatitis C virus (HCV) infection is also a risk factor.³ 

Autoimmune diseases

In most cases, MALT lymphomas that occur in the lungs, thyroid gland and salivary glands are linked to autoimmune conditions, including Sjögren’s syndrome and Hashimoto’s thyroiditis. Autoimmune diseases are caused when the body’s immune system attacks its own healthy cells and tissues.³

Changes in the DNA: the genetic side 

What are genetic changes?

It refers to a change in the DNA sequence of an organism. There are two kinds of genetic mutations: germline and somatic. Germline mutations are inherited and passed on to offspring. They occur in reproductive cells (eggs and sperm). Somatic mutations are acquired and can be caused by environmental factors like infections, toxins or pollution in the environment, radiation exposure or ageing. Somatic mutations occurring in body cells are not passed to the offspring.⁴ 

Common DNA changes seen in MALT lymphoma

Chromosomal translocation is a type of genetic alteration in which a piece of one chromosome breaks off and attaches to another chromosome. It is recurrent in MALT lymphomas and varies depending on the site of disease. For instance, the t(11;18) translocation is associated with antibiotic therapy resistance in gastric MALT, which necessitates alternative treatments.⁵

The most common translocations that cause MALT lymphoma are listed below:⁵

• t(11;18)(q21;q21)
• t(1;14)(p22;q32)
• t(14;18)(q32;q21)
• t(3;14)(p14.1;q32)

Modification of a base pair of a DNA sequence in a gene is called a mutation. It can be a deletion, insertion or duplication of a nitrogenous base pair. Some of the commonly found mutations in MALT lymphomas are found in genes B2M, P300, TNFAIP3, TET2, SPEN, CREBBP, KMT2C, KMT2D, LRP1B, PRDM1, E, TNFRSF14 and NOTCH1/NOTCH2.⁵  

The presence of an extra copy of a chromosome resulting in an abnormality is called trisomy. Many cytogenetic studies have reported that trisomy of chromosomes 3 or 18 is prevalent in MALT lymphoma.

Table 1:  Common genetic aberrations detected in MALT lymphomas ⁵  

Key molecular mechanisms involved

The NF-κB pathway: The master switch

NF-κB is a transcription factor that plays a pivotal role in cellular processes, including inflammation, cell proliferation, apoptosis, and immune responses. It induces the expression of various pro-inflammatory genes. It also contributes to regulating the activation, survival, and differentiation of lymphocytes. Studies reveal that genetic mutations activate NF-kB in MALT lymphoma.⁶

B-Cell receptor signalling

The B-cell or the B-lymphocyte is part of the immune system, and it produces antibodies. It also secretes cytokines involved in immune regulation. BCR signalling is an important pathway for B-cell malignancy. In addition, B-cell lymphoma can be induced by BCR through chronic activation of foreign microorganisms or viral antigens. This includes mucosal lymphoid tissue lymphoma induced by Helicobacter pylori.⁷

Epigenetic changes

The effect of the environment and behaviour of a person on genes is known as epigenetics. It does not alter the DNA sequence, but influences the gene expression. Hence, epigenetics can regulate whether a gene is turned on or off. The most common mechanisms behind epigenetics are DNA methylation and histone modification.⁸

The impact of genetic changes on treatment

Why do some patients respond to antibiotics?

Antibiotics are usually the first line of treatment in case of MALT lymphoma. Patients respond if there is no underlying influence of any genetic mutation. If traces of lymphoma still remain after antibiotic treatment, radiotherapy or chemo-immunotherapy can be done along with active monitoring.⁹

New treatments based on genetics

Several genetic studies have contributed to the improvement of drug design and discovery. Current developments in next-generation sequencing (NGS) and the human genome project have given remarkable insights into genomic alterations behind tumour biology, oncogenesis, and survival. For instance, efforts are being made through extensive research studies and trials to develop NF-κB inhibitors for cancer treatment.⁵

Personalised medicine

Personalised medicine is tailored to an individual’s genetic profile for the prevention, diagnosis, and treatment of disease. Next-generation sequencing is now used to sequence the DNA of patients’ tumours. This helps in designing therapies that target specific genetic alterations causing tumour growth.⁵

Summary 

Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of marginal zone lymphoma. It is often caused by chronic infection or inflammation and can occur on different sites of the body (gastric and non-gastric). There are complex genetic and molecular changes which induce the disease. Understanding these changes can lead to better diagnosis, treatment, and outcomes. Several research studies are being conducted to discover more precise and effective therapies and treatments. Interestingly, recurrent genetic alterations have been characterised which affect many common pathways of molecular mechanisms behind the disease. Epigenetic studies and gene expression profiles have given useful insight, which can contribute immensely to designing novel drugs and therapies.

FAQs

What is the difference between MALT lymphoma and lymphoma? 

Unlike various other types of lymphoma, MALT lymphoma typically develops outside the lymph nodes. Also, it does not usually cause swollen lymph nodes. 

What is the most common site of MALT lymphoma?

It mostly occurs in the stomach, called gastric MALT. It may also develop in the thyroid, lung, salivary glands, skin, eye or soft tissues.

What is the five-year survival for most patients with MALT lymphoma?

Disease-free survival for MALT lymphoma is estimated to be 77% to 80%. 

What is a MALT lymphoma transformation?

It is called low-grade Lymphoma because of its slow-growing characteristic. However, low-grade lymphomas can convert to faster-growing (high-grade) lymphoma, known as transformation.

Does MALT lymphoma cause fatigue?

Individuals with gastric MALT lymphoma may feel fatigued or have anaemia caused by bleeding in the stomach.