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Running Head: CRITICAL ANALYSIS OF HERITABILITY: GASTROINTESINAL CANCERS

A critical analysis of the current or suggested evidence pertaining to the heritability of Gastrointestinal cancers Samriti Mishra University of Waterloo

2 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS Abstract Gastrointestinal cancers are one of the most commonly occurring neoplasms of contemporary times. Both sporadic and predisposing syndromes contribute to the incidence rates of gastrointestinal cancers. Hence, there is an increasing need for screening and correctly identifying genetic and familial cancer syndromes in the field of Oncology. The following review is an attempt to identify and update the current and suggesting knowledge pertaining to the heritability of gastrointestinal cancers by checking and cross checking references of primarily a recent systematic review on this topic. It was found that the sample for most of these retrospective cohort case studies was less than 50 subjects, which may imply low external validity. However, as this field is catered to familial genetic cases, this may not reduce the power of the study. The results have positive implications for genetic screening in high-risk patients, who have a positive familial history, an abnormal immunohistochemistry or high density polyposis. Keywords: Gastro-intestinal cancer, complex genetic trait, chromosome aberrations, chromosome disorder, gene rearrangement.

3 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS In the last few decades, anticipation around how human genetics can lead us towards predictive and preventive medicine has spurred intense researches like the Human Genome Project. As a result, the clinical sciences have the added dimension of genetics towards the prognosis of a given disease. Gastric cancer is one of the most commonly occurring malignant neoplasms worldwide, and remains a leading cause of cancer death in Asia and some European countries (pg.241, Yamamoto et al., 2011). To further understand the significance, Pollock and Welsh mentioned the term oncogenetics, which encompasses the science linking all aspects of genetics including predisposition, genetic testing, treatment outcome, potential morbidities and tumors natural history to the management of cancer. Analyzing the pathophysiology of gastrointestinal cancers and a clear understanding of the genetic predispositions will help clinicians predict how aggressive the treatment should proceed. Extensive studies of colorectal cancer (CRC) have identified etiologies specific to genetic changes in various proto-oncogenes, tumor suppressor genes and DNA mismatch repair genes, as well as alterations in DNA methylation status and inherited genetic defect (Heavey & Rowland, 2004). There are at least four categories of mutations that can contribute to the acquisition of tumor phenotype, namely: 1) Mutations in the genotype resulting in abnormal products, an example being H-rasi and K-ras gene mutation resulting in amino acid changes at 12 or 61 in the protein. 2) A mutation resulting in an overproduction of an oncoprotein, an example being the immunoglobulin gene-myc chromosomal translocation observed on Burkitts lymphoma, resulting in the overproduction of a normal myc protein, important for tumor growth. 3) A loss of function mutation. In 75% of human colorectal carcinomas, one allele at 17p12 chromosomes is deleted, which contains the p53 gene, important for tumor suppression. 4) The mutation resulting

4 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS in amplification of an oncogene. The oncogene N-myc is amplified in neuroblastoma and is associated with a poorer prognosis (Barletta et al., 1993). The heritability of gastrointestinal cancers is not thought to have been underestimated in the past, as recent data suggesting that up to 25% of patients may have a personal or family history of an inherited syndrome. The red flags of cancer predisposition vary by syndrome but common denominators include strong family history, prior personal history of cancer, atypical presentation, suggestion of an autosomal dominant inheritance pattern and family members diagnosed at unusually young age (Pollock & Welsh, 2011). Some of the important genetic terminology used in this paper are defined as follows. Tumor suppressor genes function to suppress tumorigenesis and control cell proliferation. Pollock and Welsh explain that there are two main categories of these genes; 1) caretaker genes are responsible for genomic integrity and 2) gatekeepers genes which control the gates to cellular proliferation. A loss in gatekeeper activities directly affects the cell proliferation rate, while a loss in caretaker activity increases the chances of mutations resulting in an indirect contribution to abnormal cell growth. Further, gatekeeper related cancer syndromes are inherited in an autosomal dominant pattern, while caretaker related cancer syndromes are inherited in an autosomal recessive pattern. All tumor suppression genes require two inactivating mutation to yield the diseased phenotype. Percentage of penetrance refers to the probability of the other allele sustaining an inactivation mutation, ultimately resulting in malignant transformations. Colon polyp, which is used though-out this review as a key diagnostic feature of various syndromes, is defined as a small clump of cells that forms on the lining of the colon, which, depending upon size and severity can become cancerous over time. While colon development is commonplace, high risk individuals are over 50 years of age, are overweight, smokers, ingest a

5 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS high-fat, low-fiber diet, or have a personal or family history of colon polyps or colon cancer (Mayoclinic, 2011). Given the plethora of information around cancer, it is important to cater to individuals who are concerned about the heritability of gastrointestinal cancers and the possible prevention or screening implications for them. A literature review was performed on published literature regarding the basic pathophysiology and heritability of gastrointestinal cancers, (specifically gastric cancer, esophageal cancer, Juvenile Polyposis syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis and Lynch syndrome) to gauge the current understanding and treatment protocols for them. Methodology Published literature was reviewed by searching Scopus and PubMed. In Scopus the terms Gastro-intestinal cancer AND Genetic* OR Complex trait* OR Complex Genetic Trait* were searched within Article titles, Abstract and Keywords, resulting in 545 articles. The search only included articles from the Health and the Life science categories; Physical and Social science were excluded. The restriction of document to reviews and articles resulted in a total of 497 articles. As a recent article was desired, the result was sorted by date. The most recent and the broadest articles were selected for basic information purposes. The different articles were chosen on the diversity of the perception taken on the subject such as various clinical approaches, various understandings of DNA methylation of the gene believed to be responsible and various implications for gene therapy. Scanning was done primarily by article abstracts and topic headings. Preference was given to the article with higher number of citation, if there were more than one article on a particular subject. The first 200 articles were scanned, with duplicated

6 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS being removed (via higher number of citations) and loose clustering of various perspectives with which the author tackled gastrointestinal cancers. Any articles which did not take into account the back-ground information, gastro-intestinal cancer, or genetic component and/or physiological aspects of the disease were excluded. I tried to search for more than one particular gene described in the article; multiple articles about the same gene were excluded. A total of 15 articles were selected, three of which were discarded after being read in detail because the main focus was pancreatic cancer or had excessive physiological basis/mechanism. The final total number of articles, which included six literature reviews, four experimental studies and one each of description or associative studies, resulted in 12 articles. Most were retrieved from either PubMed or Scopus from online resources, while four were ordered via inter-library loans. The final analysis was primarily based on the review of the 4 literature reviews Clinical Cancer Genetics Part 1: Gastrointestinal, which was published in year 2011, DNA methylation marker in patients with gastrointestinal cancers: Current understanding, potential applications for disease management and development of diagnostic tools published in 2003, Gastrointestinal cancer: Best practice and Research: Clinical Gastroenterology published in 2004 and Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. Addition articles were used from the reference from the Clinical Cancer Genetics Part 1: Gastrointestinal article by Pollock and Welsh, along with some information from the other review DNA Methylation Markers in Patients with Gastrointestinal Cancers. While trying to retrieve the articles from Pubmed, the following MeSH terms were noted: chromosome aberrations, chromosome disorder and gene rearrangement. This may be used for future research on the subject.

7 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS Results The results from all the following syndromes and cancers have been summarized (in table 1.) can be found at the end of the article. The more detailed results from each of the subcategory of gastro-intestinal cancers are as follows. Hereditary diffuse gastric cancer (HDGC) HDGC is an inherited autosomal dominant mutation which predisposes to a diffuse, poorly differentiated gastric adenocarcinoma (Pollock & Welsh, 2011). The International Gastric Cancer linkage Consortium (IGCLC) defined the syndrome of HDGC as any family fulfilling one of the following criteria: (1) two or more documented cases of diffuse gastric cancer in first/second-degree relatives with at least 1 diagnosed before the age of 50; or (2) three or more cases of diffuse gastric cancer in first/second-degree relatives, independent of age. It has been predicted that up to 25% of families identified by these definitions would have the inactivating germline CDH1 mutations. Families with aggregation of gastric cancer and an indexed case with diffuse gastric cancer, but not fulfilling the above criteria are termed as familial diffuse gastric cancer (FDGC). E-cadherin, encoded by the CDH1 gene that maps to chromosome 16q22.1, which is a calcium dependant cell adhesion molecule mostly expressed in the epithelial tissues. The CDH1 inactivation pertains to the loss of the caretaker activity of E-cadherin, contributing to tumorigenesis. In countries with high incidence rates of HDGC, insignificant number of percentage of families selected by the criteria was found to carry the mutation. This may be suggestive of a cumulative effect of environmental risk factors namely, virulent Helicobacter pylori strains and genetic susceptibility (Oliveira, 2006). A decrease in the Gastric pH levels results in longer survival of the gastric flora and proliferation. H. pylori a Gram-negative

8 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS bacterium has several mechanisms associated with carcinogenesis in humans, namely, disregulation of gastric epithelial cell cycle, formation of DNA adducts, generation of free radicals, alterations in growth factor secretion and cytokines and the effect of decreased gastric secretions. On experimenting with the effect of H. pylori on the role of p53 (a key tumor suppressor gene), it was found that there is a dose-response dependent inhibition of cell growth and apoptosis. Along with the inflammatory effects of H. pyloric infection, causing increased cell proliferation, production of mutagenic free radicals and N-nitroso compounds, it was also associated with changes in oncogene, tumor suppressor gene expression and disregulation of cell cycle proteins. High dose vitamin C has been shown to inhibit H. pylori growth and a reduced risk of gastric cancer. Overexpression of cyclo-oxygenase-2 (COX-2) is implicated in a number of cancers and those with the bacteria has significantly higher expression. Epidemiological studies have indicated that improved nutrition, water supply and reduced family sizes are associated with reduced H. pylori colonization. (Heavey & Rowland, 2004). It is worth noting here that while the original systematic review indicated a lack of association of the bacterial colonization and HDGC, other studies have found a positive correlation (Yatamoto et. al., 2011) (Coroso et. al., 2011). Juvenile Polyposis syndrome Juvinile Polyposis syndrome (JPS) is a grade of harmartomatous (wherein the abnormality results from deviant development of an organ) is termed Juvenile because of polyp characteristic rather than age of presentation. This is a unique cancer, where in the genetic mutations are interrelated to the mutations found commonly in breast and pancreatic cancers, and has significant gastrointestinal malignant potential (Chow & Macrae, 2005). This is referred to as genetic heterogeneity, wherein two different genes cause the same disease as well as the

9 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS complimentary concept in which different mutations in the same gene can cause different disease. Most cases of JPS are sporadic. The diagnostic criteria for JPS are: More than 5 juvenile polyps of the colon or rectum or; Juvenile polyps in other parts of the gastrointestinal tract, or; Any number of juvenile polyps and a positive family history

Most patients with JPS have 50-200 polyps distributed throughout the colon. JPS is an autonomous dominant condition with incomplete penetrance. Two specific genes SMAD4 (the human counterpart for Mothers against decapentaplegic, Drosophila homologue 4) and BMPR1A (Bone morphogenetic protein receptor 1A), have been identified. Mutations in these result in disturbance in the pathway of transforming growth factor (TGF ) signal transduction pathway. This pathway mediates growth inhibitory signals from the cell surface to the nucleus. SMAD4 germline mutations were first identified through linkage analysis in five out of nine JPS patient in 1998 (Chow & Macrae, pg. 1636, 2005). BMPR1A is a gene upstream from SMAD4. It encodes for a type I serine/threonine kinase receptor that belongs to the TGF receptor. When the BMPR1A is activated it phosphorylated SMAD family resulting in complexes that travel to the nucleus to moderate the transcription of DNA sequence. (Chow & Macrae, 2005). Approximately 20% of patients with JPS will develop CRC by age 35 and upto 68% will develop it by age 60. Gastric cancer has been reported in upto 21% of patients with JPS. Increase risks of small intestinal and pancreatic cancer has also been observed (Pollock and Welsh, 2011). Findings suggest that upon detection of mutation, at risk family member should undergo regular check-ups and genetic screening. After disease progression endoscopic polypectomy, subtotal/total gastrectomy is performed.

10 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS Peutz-Jeghers syndrome This is a hamartomatous gastrointestinal multiple polyposis, with a significantly high risk of developing cancers, both gastro-intestinal and non-gastro-intestinal. It is also morphologically symptomatic; hyperpigmentation may be found on the buccal mucosa, lips, fingers and toes (Podratz et al, 1998). Small, flat, brown or dark blue spots that look like freckles are commonly observed in the peribuccal area and cross the vermillion border of the lips (Pollock and Welsh, pg. 334, 2011). As a measure of the seriousness of the disease, relative risks of colon, stomach and small intestinal neoplasms have been estimated as high as 84%, 213% and > 500% respectively. Overall, PJS is associated with very high risk of cancer the cumulative risk being 93% between the ages of 15 to 64 years in those who have the syndrome. According to relativerisk analysis, the observed development of cancer in the patients with the syndrome was 18 times greater than expected in the general population (P<0.0001) (Giardiello et. al., 1987). PJS has an autosomal dominant pattern of inheritance, with different levels of penetrance. The mutation occurs on STK11 (for serine/threonine kinase 11) for tumor suppression gene on chromosome 19p13.3 (Pollock & Welsh, 2011). An intensive screening program including at least the colon, breast and cervical cancers is appropriate with persons diagnosed with this syndrome (Boardman et al, 1998). Familial Adenomatous Polyposis Familial Adenomatous Polyposis (FAP) accounts for about 0.5% to 1% of all Colorectal cancer (CRC). It has an autosomal dominant inheritance pattern with 100% penetrance. Patients with FAP have a virtual certainty of developing CRC by age 60 (Pollock & Welsh, 2011). It is characterised by hundreds or thousands of adenomatous (benign) polyps by age 20 years. FAP

11 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS results from mutation in the APC (Adenomatous Polyposis Coli) gene, located on the chromosome 5q21-22. APC is a tumor suppressor gene of the gatekeeper variety and the its functional loss results in uncontrolled cell proliferation, leading to malignancies. It is in involved in the wnt pathway which controls the levels of -catenein, which promotes cell proliferation. When the destruction complex which binds to -catenein is not formed, -catenein is then free to stimulate cell growth by turning on several genes involved in the cell cycle. FAP may also be related to low (~ 2%) incidence of thyroid cancer, stomach cancers, duodenal and pancreatic cancer. Genetic testing and rigorous screening is the protocol for patients who have a positive family history and diagnosed with FAP, on an annual or biannual basis. After polyps become too numerous for endoscopic management, there are three surgical options available: colectomy with ileorectal anastomosis (IRA), restorative proctocolectomy, or pouch procedure, and proctocolectomy with permanent end ileostomy (Christopher et al, 2005). Hepatoblastoma in early paediatric age (age 5 year or less) is another malignancy sometimes identified with FAP (~ 1.6%) wherein the recommended screening by alpha-fetoprotein monitoring and hepatic ultrasound is standard. Lynch syndrome As explained by Pollock and Welsh in their review, Lynch syndrome or hereditary nonpolyposis colon cancer is the root cause of 5% of CRC. It is noted that mutation in genes that control DNA mismatch repair are known causes. This mutation pertains to correction of the A-T and G-C base pairs in the double helix, which are not properly repaired during semi-autosomal replication processes. The commonly mutated genes in Lynch syndrome are MLH1, MSH2, MSH6 accounting for more than 95% of all known Lynch syndrome-associated mutations, along

12 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS with PMS2 showing pathogenic germline mutations. This is a caretaker gene activity impairment, which oddly exhibits autosomal dominant pattern of inheritance (rendering susceptibility) with 80% penetrance. They are all involved in signalling damage-induced apoptosis and their inactivation would increase the occurrence of mutations but also promote cell growth, resulting in tumors (Peltomaki, 2004). Lynch syndrome almost always demonstrates microsatellite instability (i.e. how frequently certain site of DNA repetition satellites, contain errors). While this in of itself is not exclusively a symptom for Lynch disease (10% of sporadic cancers also share the MSI), it does have implication for treatment protocol, as it respond to 5flurouracil based chemotherapeutics. Hence, at patients tertiary referral centers and people with strong family background of the disease are screened for microsatellite instabilities or immunohistochemistry for mismatch repair gene mutations. On testing positive, genetic screening is considered appropriate (Pollock & Welsh, 2011). Discussion The current evidence suggests that Gastro-intestinal cancers have variable heritability depending up on the specific type of cancer. Without exceptions however, the discussed gastrointestinal cancers have a genetic mutation triggering the conditions, rendering genetic screening and intervention at genetic levels valid. Specifically, genes responsible for tumor suppression undergo functional loss, resulting in uncontrolled cell proliferation with malignancy potential. However, the literature review is conflicted on some key etiologic phenomena. For example, while the original article by Pollock and Welsh being review indicted that typically HDGC is not associated with Helicobacter pylori colonization, it has been shown in previous studies that there is a positive correlation (Heavey & Rowland, 2004). It is also worth noticing that with the exception of PJS, most experimental studies were retrospective case-control and

13 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS some prospective case-control studies. As with case-control studies conducted with rare disease, the application of the findings outside of the target populations is questionable. Hence there are clear threats the external validity of these findings. This has implications for genetic screening, as it is unclear to what level and extend should it be applied. The flip side is that because the diseases are rare, the sample sizes do not have be very large to determine a correlation or even causation. While the rarer conditions of PJS, JPS and FAP, a positive family history and progressing age do warrant genetic screening and regular endoscopic examinations, it remains unclear in the more common cancer of the gastrointestinal tract. An observed strength of the reviews was that the experimental studies upon which the literature reviews were based, were consistent when compared with other similar studies, rendering strong face validity to the current body of knowledge. The reviews might be vulnerable to selection bias, as using the term genetics restricts preventative measures. Diet, anti-oxidant intake and less invasive protocols should also be an important part of cancer management, which is mostly omitted from the treatment as per these reviews. There are some limitations of the review conducted here. While it is quite exhaustive in covering different gastrointestinal cancers, more evidence and knowledge in each of these disease is required to draw a more comprehensive picture of the current conditions. Further, the keywords using genetics in the search term biases the search results here as well; only studies done with genetic components would show up. This provides an incomplete picture of the heritability of gastrointestinal cancers. The large percentage of the cancers which dont have genetics in their respective etiology would be not included. Ideally, a search of each of these individual diseases should be conducted across databases. In essence, each disease has enough body of knowledge to warrant individual literature reviews. Once each disease is tackled at all

14 ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS levels of interventions possible, the overall picture, interaction effects would come to light. Future research should be in the field of condensing all the current knowledge and making the research findings more applicable to the general population. This is of paramount importance to clinicians who have to deal with cancers on a daily-basis, so that the decision making is in the patients best interests. When the knowledge of the cancers can be comprehended, further prevention programs can be put in place, plans can be set in motion and no stone left unturned to meet the end result of eradicating the biggest threat to mankind in this century cancers.

Type of Gastrointest inal cancer Risk Heritability statistics Implications for treatment protocol

Level of intervention

Mutation type

Lynch syndrome n/a

Gene/Cell level, histopathology considered 5% of all Colorectal cancers. 80% penetrance

MLH1, MSH2, MSH6 account for 95% of the cases

Screened for Microsatellite instabilities, if positive formal Genetic screening.

Familial adenomatous polyposis APC nonsense mutation resulting in loss of function n/a

Gene/Cell/Organ level, surgical removal of polyps

If diagnosed, virtual certainty, 100% penetrance

Genetic screening, endoscopic surveillance and colectomy

Table 1 : Summary table for gastrointestinal cancers

ANALYSIS OF HERITABILITY: GASTROINTESTINAL CANCERS

Peutz-Jeghers syndrome

Gene/Cellular level, Primary level of intervention, including screening followed by necessary clinical measures. Rare in approximately 1 in 8300 to 29 000 live births. Once diagnosed, very high risk of developing some kind of cancer. Mutation in STK11 tumor suppressor gene on chromosome 19p13.3

53% of patients developed some kind of cancer. (n=34)

Patients with PJS should receive regular screening for colon, breast and cervical cancer. The screening should be tailored to the age of the patient.

Juvenile polyposis syndrome

Organ level, endoscopic polypectomy, subtotal/total gastrectomy. Rare, in about 2% of children and adolescents. Prevalence of 20% in germline mutations

Mutations in the SMAD4 (MADH4 and DPC4) and Non-sense mutation in BMPR1A causing disruption of TGF pathway

41% of patients were positive for either both or one of the mutations (n = 54)

Findings suggest that upon observation of mutation, at risk family member should undergo regular checkups and genetic screening. Missense mutation at 16p on 9p12 gene sequence. For tylosis A gene is localized on band 17q25, name TOC. 38% of the patients showed p16 promoter hypermethylation with LOH (n = 21) Findings suggest that treatment with demethylating agents at the RNA expression level.

Esophageal cancer / Barretts esophagus / Tylosis A

Gene/Cell/Organ level, administration of Demethylating agents

Type A Tylosis is inherited in an autosomal dominant fashion, with 95% risk by age if 65 years.

Gastric cancers / Hereditary diffuse Gastric Cancer (HDGC)

Gene/Cell/Organ level, Prophylactic Gasterctomy/control of H. pylori colonization

Cumulative risk by age 80 years is 67% for men and 83% for women. Germline mutation accounts for about 30% of the cases

Truncating or missense mutation for CDH1 gene, encoding for E-Cadherin

30-40% of the HDGC families screened were found to harbor germline deleterious mutations (n= < 40)

Findings suggest that prophylactic (total) gastrectomy should be considered as a valid approach for management of asymptomatic HDCG.

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