Analysis from a recent study has found that loading up on snack foods may increase cancer risk in individuals with an inborn susceptibility to colorectal and other cancers. Published early online in Cancer, a peer-reviewed journal of the American Cancer Society, the study suggests that an eating pattern low in snack foods could help these individuals — who have a condition called Lynch syndrome — lower their risk.
Lynch syndrome is an inherited condition characterized by a high risk of developing colorectal cancer, endometrial cancer, and other cancers at an early age. The syndrome is caused by mutations in genes involved with repairing DNA within cells.
Numerous studies have investigated associations between certain foods and colorectal cancer, and now there is general agreement that red and processed meats and alcohol consumption can increase individuals’ risk. Only a few studies have evaluated lifestyle factors and colorectal cancer in patients with Lynch syndrome, though. To investigate, Akke Botma, PhD, MSc, of the Wageningen University in the Netherlands, and her colleagues collected dietary information from 486 individuals with Lynch syndrome. During an average follow-up of 20 months, colorectal polyps (precancerous lesions) were detected in 58 people in the study.
“We saw that Lynch syndrome patients who had an eating pattern with higher intakes of snack foods — like fast food snacks, chips, or fried snacks — were twice as likely to develop these polyps as Lynch syndrome patients having a pattern with lower intakes of snack foods,” said Dr. Botma.
The findings suggest that certain dietary patterns have an influence on the development of polyps in individuals with Lynch syndrome. “Unfortunately, this does not mean that eating a diet low in snack foods will prevent any polyps from developing, but it might mean that those Lynch syndrome patients who eat a lot of snack foods might have more polyps than if they ate less snack foods,” said Dr. Botma. Because the study is observational, other studies are needed to confirm the results.
Previous work from the group revealed that smoking and obesity may also increase the risk of developing colorectal polyps among individuals with Lynch Syndrome. Thus, even though they may have inherited a very high risk of developing cancer, it may be possible to affect this risk by adopting a healthy lifestyle, including a healthy diet.
Akke Botma, Hans F. A. Vasen, Fränzel J. B. van Duijnhoven, Jan H. Kleibeuker, Fokko M. Nagengast and Ellen Kampman. Dietary patterns and colorectal adenomas in Lynch syndrome : The GEOLynch Cohort Study. Cancer, 2012; DOI: 10.1002/cncr.27726
polyps of the colon and rectum. Estimates of the population prevalence of Juvenile Polyposis syndrome suggest a frequency of around 1:100 000. It accounts for less than 0.1% of all colorectal cancer cases.(JPS) is defined by the presence of multiple hamartomatous
Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between this disorder and (PJS). Juvenile hamartomatous polyps have an apparently normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria with smooth muscle fibres, which distinguishes these from PJS polyps. The glandular proliferative characteristics of adenomas are typically absent.
The term ‘juvenile’ refers to the polyp type rather than to the age of onset, although most individuals with juvenile polyposis have some polyps by 20 years of age. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. Juvenile polyposis usually manifests during childhood, but diagnosis of the condition is confounded by the occurrence of isolated juvenile-type polyps in children. These solitary polyps are noteworthy because their identification in childhood does not necessarily indicate a heritable cancer predisposition syndrome, and they do not appear to be associated with excess cancer risk. In contrast, juvenile polyposis is associated with a colorectal cancer risk of around 10-38% and a gastric cancer risk of 21%.
If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk of GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported.
Around 20% of cases are due to mutations in the SMAD4 gene, while a further 20% are due to mutations in another gene in the same TGF-beta molecular signaling pathway, BMPR1A, indicative of genetic heterogeneity. Mutations in BMPR1A have been particularly implicated in European populations and SMAD4 mutations may have a more aggressive clinical phenotype. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4 mutation.
JPS is clinically diagnosed if any one of the three following findings is present:
Testing relatives at risk: When the family-specific mutation is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention.
UK BSG Screening Guidelines
< Large bowel surveillance for at-risk individuals and mutation carriers every 1-2 years is recommended from age 15-18 years, or even earlier if the patient has presented with symptoms. Screening intervals could be extended at age 35 years in at-risk individuals. However, documented gene carriers or affected cases should be kept under surveillance until age 70 years and prophylactic surgery discussed. The intervention should visualise the whole colon and so colonoscopy is the preferred modality. Although isolated juvenile polyps are relatively common, juvenile polyposis is rare and consequently experience is limited. There are few large descriptive studies, and no comparative study to demonstrate potential benefit. Nonetheless, there is a substantial risk of colorectal cancer amounting to 10-38%. Many polyps are located in the right colon, and so the whole colon should be visualised. There is particular risk of malignancy in cases where there is adenomatous change, or where there is a dysplastic element to the polyps.
Upper gastrointestinal surveillance
< Upper gastrointestinal surveillance every 1-2 years is recommended from age 25 years, contemporaneously with lower gastrointestinal surveillance. The risk of gastric and duodenal cancer in juvenile polyposis is round 15-21%.
The hyperplastic polyp and serrated adenoma pathway
The first series of mixed hyperplastic-adenomatous polyps were described in 1990 (Longacre and Fenoglio-Preiser 1990), and have been an increasingly recognised phenomenon. Most hyperplastic polyps have no malignant potential, although there is now some have malignant potential, especially those with serrated architecture (sessile serrated adenomas – SSAs), large hyperplastic polyps, mixed polyps and polyps on the right side of the colon (Torlakovic et al. 2003).
Classification of hyperplastic polyps
A new understanding of the clinical relevance of hyperplastic polyps has emerged over the past decade (Young and Jass 2010). The simple hyperplastic polyp has itself been subclassified into a goblet cell variant and a microvesicular variant, the latter appear to be the precursors for serrated adenomas and thus colorectal cancer. Serrated adenomas usually have serrations low in the crypts which help differentiate them from hyperplastic polyps.
However, serrated polyps also include a broader spectrum of polyp subtypes ranging from these small common lesions to the recently described sessile serrated adenoma (SS
A), which is often large and proximal with abundant mucin secretion, exaggerated serration, and atypical architecture. Rarer serrated polyp subtypes with unequivocal dysplasia include traditional serrated adenoma (SA), which combines the dysplastic features of an adenoma with the architectural features of a hyperplastic polyp and the mixed polyp (MP) in which separate hyperplastic and dysplastic elements are combined within a single polyp (see figure). SSA, SA, and MP are described as “advanced serrated polyps” and comprise ∼5% of all serrated polyps retrieved in colonscopy patients. Importantly, these advanced serrated lesions show frequent BRAF mutation and widespread DNA methylation.
Endoscopic appearances of serrated adenomas
Serrated and hyperplastic polyps present endoscopic features that could help to differentiate them from adenomatous polyps. HPs appear flat and pale and are often covered by a thin film of mucus. They exhibit Kudo type 2 pit pattern typically. As they are not highly vascular they will appear pale compared to surrounding mucosa using narrow-band imaging (NBI). In addition, chromoendoscopy may be helpful in the endoscopic characterisation of these lesions.
Inherited Colorectal Cancer Syndrome?
An inherited hyperplastic polyposis syndrome (HPS) has also been increasingly recognised (Cohen et al. 1981; Sumner et al. 1981). It is now more commonly known as serrated polyposis syndrome. There is no sex predominance and the mean age at diagnosis is around 55 years. HPS has largely been considered a genetic disease, but the pattern of inheritance remains unknown: both autosomal recessive and autosomal dominant patterns have been suggested. Environmental factors could be partially responsible for the phenotypic differences and model the unknown pattern of inheritance. Smoking, being overweight and some drugs have been postulated as potential risk factors of HPs.
In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC (Ferrandez et al. 2004; Young and Jass 2006). Boparai et al (2011) have recently described an increased risk of CRC [relative risk (RR) = 5.4] and HPS (RR = 39) in first-degree relatives of probands diagnosed with HPS compared to the general population. Estimates for CRC risk associated with serrated polyposis may range from 7% to 50% and vary with phenotype.
Classification of the Syndrome
In the WHO criteria, Burt and Jass defined HPS as at least five HPs proximal to the sigmoid colon, two of which are > 1 cm diameter, or more than 30 HPs at any site in the large bowel (Burt 2000). Rashid et al, however, used a different classification system, in which HPS was defined as any person with more than 20 HPs, and separate classes were used for patients with large (>1 cm diameter) or multiple (5-10) HPs (Rashid et al. 2000). These differing classification systems reflect a syndrome which may be both genetically and phenotypically heterogeneous, but one which is becoming increasingly recognised.
The serrated pathway to colorectal cancer
Some evidence suggests that some but not all of these tumours develop along a ‘serrated pathway’ separate from the classical adenoma-carcinoma sequence (Sawyer et al. 2002; Spring, Zhao et al. 2006). This serrated pathway involves one group who accumulate BRAF V600E mutations and another separate pathway which involves KRAS mutations(Carvajal-Carmona et al. 2007). In addition the tumours often have methylation of the MLH1 promoter with subsequent microsatellite instability, and other genes such as P16, MGMT, or IGFBP7 may also be epigenetically inactivated. The CIMP phenotype identified by increased levels of methylation in the CpG island marker MINT31(Jass 2005).
HPS (sometimes known as the ‘serrated pathway syndrome’ or ‘serrated pathway syndrome’ (SPS) and sometimes ‘Jass Syndrome’) may, in fact, be a heterogeneous group of conditions leading to sporadic and inherited cases of colorectal neoplasia. There are two alternative clinical criteria for the diagnosis of HPS families (Burt 2000; Rashid, Houlihan et al. 2000). This syndrome is usually associated with somatic mutations in either BRAF or KRAS, but not both together (Carvajal-Carmona, Howarth et al. 2007), providing further evidence of molecular as well as phenotypic heterogeneity. BRAF mutations are associated with low-grade microsatellite instability due to methylation in CpG islands (CIMP)(Young, Jenkins et al. 2007). This may result in loss of expression of DNA repair genes MLH1 and MGMT (O(6)-methylguanine-DNA methyltransferase) in dysplastic mixed polyps from HPS patients, possibly as a result of promoter methylation (Oh et al. 2005).
Linkage analysis in a large family affected with hyperplastic polyposis syndrome demonstrated a maximum parametric LOD score of 2.71 on the short arm of chromosome 8 (8p.21; Monahan et al 2007). Another group have identified genetic linkage to chromosome 2q32.2-q33.3 with a LOD score of 2.07 (Roberts et al 2011 Fam Cancer).
As of this time however, there is no known causative germline mutation responsible for this condition, therefore genetic testing for predisposition is not possible. Because the natural history of HPS is poorly understood, colonoscopic screening guidelines have not been developed. Empirically we recommend 5 yearly colonoscopic screening from the age of the earliest known affected relative, or from 45 years of age.