Oesophageal cancer is the seventh most common cause of cancer-related mortality among males, thus exhibiting a strong male predominance attributed to environmental factors, such as alcohol consumption, cigarette smoking, nutrition and socioeconomic status (36). Apart from the environmental factors, the risk of developing this type of cancer can increase due to underlying disorders, such as gastroesophageal reflux disease (GERD), CD, Barrett's oesophagus, achalasia and obesity. Cancer generally develops in the inner layer of the oesophageal wall and continues to spread to the outer layers. According to the cancer statistics, the prevalence of oesophageal cancer is more common in Iran, India, Northern China and South Africa than in Western countries, such as the USA (37).

In GERD, the acid from the stomach rises to the oesophagus and damages the oesophageal tissue, causing a scar in the oesophagus. This constant insult and injury to the lower oesophageal cell lining and tissues can ultimately increase the proliferation of cells (38). A change in cell shape from squamous to columnar following GERD indicates the disruption of cell polarity, which marks the onset of cancer (39).

Patients with CD have been observed to have a high risk of developing oesophageal malignancies. It has been found that in patients with untreated CD, the delayed emptying of the stomach is quite common, and this may be an essential factor that can be linked to gastroesophageal reflux (23). The abnormal concentrations of a number of hormones related to the GIT have also been observed in untreated patients with CD. This causes a disbalance in upper gastrointestinal function controlled by neuroendocrine factors (40). Constant acid reflux from the stomach manifests Barrett's oesophagus. GFD has been shown as a valuable approach to reduce GERD symptoms (41).

Colorectal cancer is a cancer of the colon or rectum. It is the third most common type of cancer in males and the second most prevalent among females in the USA (42). The risk of developing colorectal cancer increase with age, diet and lifestyle. Apart from age, a family history also contributes to an increased risk of this type of cancer. It begins with the loss of the adenomatous polyposis coli (APC) gene present on chromosome 5q21 and the subsequent activation of the KRAS oncogene and mutations in the TP53 gene (42,43).

A previous study by Lasa et al (42) demonstrated that patients with CD have an increased risk of developing colorectal cancer. Consistent gluten exposure in individuals with CD may increase their risk of developing colorectal neoplasia (42). Golfetto et al (43) compared the count of Bifidobacterium in faecal matter and reported that patients with CD had a lower Bifidobacterium count. Bifidobacterium metabolites exhibit anticancer activity, as previously observed using the SW742 colon cancer cell line (44). This may be one of the probable causes of the increased incidence of colon cancer among patients with CD. Contrary to previous reports, other studies have not found any direct link between CD and an increased risk of colorectal neoplasia (45,46). It is crucial to note that these studies all involved patients with CD on a GFD and were compared to non-celiac, otherwise healthy controls (42,45,46). The simple fact may explain this as a high-fat, low-fibre diet has been associated with an increased risk of colorectal cancer, and celiac-associated intestinal damage may aid to reduce that risk by preventing the body from absorbing fat. Alternatively, immunological changes in the small intestine may prevent colon cancer from developing (46). Body mass index (BMI) is also a crucial factor when assessing the risk of developing colorectal cancer. Patients with CD are generally found to have a low BMI compared to healthy individuals (47,48), which acts as a protective factor when measuring the risk of CD (48). In addition, the lack of an increased risk of colorectal cancer in population research is due to a genuine average risk of colorectal neoplasia, not to greater colonoscopy and concomitant polypectomies in the celiac community (46).

SBA, also known as small bowel adenocarcinoma, is a rare form of neoplasm that accounts for <5% of all gastrointestinal malignancies (15). This type of cancer can affect all three parts of the small intestine, i.e., the duodenum, jejunum and ileum (49). Often, SBA is attributed as the ‘sibling’ of colorectal cancer due to epidemiological and clinical similarities between both types of cancers (49). This type of cancer arises first from the glandular cells on the small intestine lining and then spreads to deeper layers. Genes commonly mutated in this type of cancer include TP53, KRAS, APC, SMAD4, BRAF, SOX9, ATM, ARID2, ACVR2A, ACVR1B, BRCA2 and SMARCA4 (50). The risk factors for SBA can range from the consumption of sugar, red meat, alcohol, smoking and underlying diseases, such as Crohn's disease and CD. The main trigger factor for SBA arises due to inflammation in the small intestinal walls, which occurs following gluten consumption. This leads to damage in the villi of the small intestine. It has been reported that during the course of CD, γ-δ- and T-cell expansion increases in the small intestinal epithelium, which plays an active role in pathogenic inflammation (51).

Inflammation promotes the development of tumours. Gliadin peptides trigger the excessive release of zonulin (the protein that modulates tight intercellular junctions), leading to the disruption of the gut barrier and the disassembly of tight junctions (51). Tight junction proteins play an essential role in establishing and maintaining the apicobasal cell polarity (52), leading to alterations in cell polarity, a major driver and hallmark of oncogenesis (53). Zona occludens 1 (ZO-1) expression has been shown to be significantly reduced in patients with CD (54). ZO-1 is a tight junction protein that, along with occludin, helps maintain the barrier function. However, this downregulation has been shown to be reversed by following a GFD (54). Thus, persistent inflammation and alterations in cell morphology due to severe insults to cells increases the risk of SBA.

Lymphomas begin in the lymphatic system, where white blood cells proliferate uncontrollably. Although the disease is rare in children <5 years of age, it is the most commonly diagnosed type of cancer in teens aged between 15 to 19 years. The disease accounts for 12% of all cancer cases in this age group (55).

This is a rare type of aggressive-cell lymphoma that accounts for <5% of all GIT lymphomas, with an annual incidence rate of 0.5-1 per million subjects in Western countries (13). The incidence and temporal trend patterns differ by age, sex, race/ethnicity and geography, implying that infectious agents, environmental variables and lifestyle factors, in addition to the genetic status of the host, may play a role in the development of lymphoma. Immune modulation and persistent antigen activation are two critical pathogenetic pathways (56).

Patients with CD have a high risk of developing lymphoma. Patients with untreated CD often have a high risk of developing enteropathy-associated T-cell lymphoma (EATL) (57). Based on appearance, immunohistochemistry and genetic profile, it is divided into two types. However, type I is more frequent and strongly linked to CD, particularly when the condition becomes refractory to gluten withdrawal. The molecular mechanisms that cause EATL in the gluten-sensitive atrophic intestinal mucosa have been thoroughly investigated. Classic EATL frequently exhibits chromosomal gains at 9q33-34, 7q, 5q34-35 and 1q21-23, and losses at 8p, 13q21 and 9p21(58). Cellier et al (14) proposed that cryptic enteropathy-related T-cell lymphoma represents a transitory stage of gluten refractory disease with aberrant intraepithelial T-lymphocyte clones. The adjacent small bowel usually shows villous atrophy associated with CD (14). The use of a GFD to treat CD effectively inhibits the development of EATL. The mechanisms underlying the strong link between EATL and CD are unknown; antigen-driven T-cell proliferation and less specific pro-proliferative effects of chronic inflammation are both potential candidates (57).

Hepatocellular carcinoma is the most common form of primary liver cell cancer due to liver disease. It is the fifth most common type of cancer in males and seventh most common cancer in females, and ranks second as regards cancer-related mortality (59). The risk factors include heavy alcohol consumption, hepatitis B and C infection, diabetes mellitus and fatty liver disease (60). Celiac hepatitis is the most common form of liver abnormality in patients with CD (61). Untreated CD can lead to a disbalance between liver enzyme levels, ultimately increasing the risk of liver cancer. The mechanisms through which patients with CD develop liver cancer remain unknown. One proposition may be gut microbiota alterations (62). CD causes a decrease in the numbers of Bifidobacterium; as a result, the Bifidobacterium/Enterobacteriaceae ratio is altered, which then causes liver disease (62). Liver disease can be a threat that can lead to cirrhosis of the liver and, ultimately, cancer and gluten consumption by patients with CD can cause an inflammatory response, leading to liver scarring. The scar tissues hinder the flow of blood through that region of the liver, and eventually, the scars lead to cirrhosis of the liver, leading to cancer onset. Hence, untreated CD can increase the risk of primary liver cell carcinoma (61).

According to the WHO and the statistics released by the International Agency for Research on Cancer (IARC), as of December 2020, breast cancer is the most commonly diagnosed cancer among females (8). It has surpassed lung cancer, which used to have the highest incidence worldwide. Breast cancer remains the most common form of cancer in females in the USA, with 1 out of 8 women bearing the risk of developing breast cancer at some point in their lives (63). In breast cancer, the epithelial cells residing in the breast (preferably in the lobules) lead to the formation of a tumour. The risk factors for breast cancer include age, sex, lifestyle, food, sleep patterns, hormone status (oestrogen and progesterone), and inherited genetic mutations from family members. Breast cancer comprises four types, namely invasive ductal carcinoma, invasive lobular carcinoma, Paget's disease and inflammatory breast cancer. The genes associated with breast cancer include BRCA1 and BRCA2. Other than these two genes, BRCA3, located on chromosome 8p11-21, exhibits mutations that give rise to sporadic disease. Inactivating mutations in TP53 are also associated with breast cancer. The inactivation of TP53 occurs not only in breast cancer, but also in all cancer types, as this tumour suppressor gene is mainly involved in the suppression of cancer cell growth (64). Other genetic mutations associated with breast cancer include the PTEN, CDH1, PALB2, CHEK2 and STK11 genes (65).

As demonstrated in the study by Askling et al (12), patients with CD have a low risk of developing breast cancer. Patients with CD often have lactose intolerance, which occurs due to a deficiency in the lactase enzyme. Lactase deficiency can lead to CD demonstrated by the H2 lactose breath test, as previously demonstrated in a retrospective study involving 54 subjects (66). Milk products contain insulin-like growth factor 1 (IGF-1) (43), which facilitates tumour growth through angiogenesis, low rates of apoptosis (a process where the damaged cells destroy themselves and macrophages eat away the debris), and a high proliferative potential leading to a higher risk of breast cancer (43). Therefore, the possible reason for the low risk of breast cancer in patients with CD is that they consume fewer dairy products due to lactose intolerance.

Additionally, women with CD have a low nutritional status due to malabsorption by villi, leading to weight loss. This can be another factor for the reduced risk of breast cancer (67). Ugalde-Morales et al (68) demonstrated the association between common shared single nucleotide polymorphisms between the two diseases mapped onto genes enriched for immunoregulatory and apoptotic processes behind the decreased risk of breast cancer in celiac disease. Another study suggested that the reduced risk may be attributed to the lower BMI in individuals with CD, as reported in anorexia nervosa (69).

According to the American Cancer Society statistics, oropharyngeal cancer, commonly known as head and neck cancer, is the eighth most common type of cancer among males (70). The majority of oropharyngeal cancers arise in the squamous. Risk factors include human papilloma virus infection, smoking and alcohol consumption. In a previous study on Swedish patients, it was found that the risk of developing oropharyngeal cancer increased to a moderate amount in patients with CD (12). Another study reported several oral health issues, such as canker sores, xerostomia (dry mouth), dental discoloration and enamel defects in patients with CD (71). The study by Askling et al (12) employed a population cohort of 11,019 patients with CD. They reported that patients with CD were at a higher risk of developing both oropharyngeal and oesophageal cancers by 2.3- and 4.2-fold, respectively (12). Thus, one answer for the risk of oropharyngeal cancer in CD is oesophageal cancer manifestation. The radiotherapy involved in treating cancer (preferably oesophageal cancer in this case) damages the salivary glands and thickens saliva, thus leading to dry mouth disease. However, the exact reason for the increased risk remains unknown. A two-fold relative risk of cancer was found due to an increased risk of cancer of the mouth and pharynx. However, the risk was increased in those taking reduced gluten, or a normal diet, with an excess of cancers of the mouth, pharynx, and oesophagus (12). Holmes et al (72) reported a significant decrease in the morbidity rate of patients with CD adhering to the GFD diet; the results of their study suggest a protective role for a GFD against malignancy in CD (72).

Endometrial cancer is a type of cancer that forms in the tissues of the endometrium (lining of the uterus). Female-related cancer begins in the hollow, pear-shaped baby-bearing organ, and the uterus is the fourth most common type of cancer among females in the USA (73). Endometrial cancers are of two types, i.e., type I, which exhibits a dependency on oestrogen, and type II, which is oestrogen-independent. (73) Type I is most common, with an occurrence rate of 85% and generally harbours mutations in KRAS, PTEN and β-catenin (73). It also exhibits microsatellite instability. Type II endometrial cancer exhibits p53 mutation and HER-2 amplification (73). The risk factors for endometrial cancer include age, tamoxifen consumption, oestrogen treatment, obesity, menstrual factors and underlying disorders, such as diabetes mellitus (73).

This type of has been found to have an inverse association with CD. The risk for female hormone-related cancers is generally reported to be low in patients with CD (67). One reason for this may be the low exposure to oestrogen, which acts as a protective shield for these types of cancer in women with CD (67). A previous study reported that untreated CD can lead to early menopause in women, which eventually leads to low oestrogen levels in the body as ovaries begin to lose their ability to produce this hormone (74). Endometrial cancer generally occurs in females >50 years of age, i.e., after menopause. The risk increases if oestrogen pills are administered post-menopause without maintaining a balance with progesterone (75). Hence, a burst in oestrogen hormone levels following menopause may be the primary reason for developing this type of cancer.

Thus, untreated CD clearly explains the negative association with endometrial cancer. However, with a proper GFD, the timing of menopause becomes normal compared to celiac-free subjects (74).

In ovarian cancer, ovarian cells divide uncontrollably, leading to the formation of tumours. Ovarian cancer is the seventh most common type of cancer among females. This cancer has a high mortality rate (76). Mutations in the BRCA1 and BRCA2 genes are responsible for this type of cancer. Apart from these genes, mutations in other genes, such as CHEK2, RAD51, BRIP1 and PIK3CA have also been observed. The risk of developing ovarian cancer increases if an individual has a family history of breast or ovarian cancer (77).

Women with CD have a lower risk of developing ovarian cancer, as reported by a study carried out in Sweden, in which 17,825 women with CD were diagnosed between the years 1969 and 2007(67). It has been observed that patients with CD have a reduced risk of developing female hormone-related cancer. A possible explanation for the reduction in ovarian cancer is that women with CD may be less exposed to oestrogen in their lifetime (67). Oestrogen displays a close association with ovarian cancer along with endometrial and breast cancer (67). The inflammation that generally arises due to this disease can cause hormonal disbalance. This condition later gives rise to issues regarding pregnancy and menopause.