Screening and surveillance for gastric cancer: Does family history play an important role in shaping our strategy?

1 INTRODUCTION

Despite the emergence of various advanced modalities in the diagnosis and treatment of gastrointestinal diseases, gastric cancer (GC) remains one of the most deadly cancers worldwide. According to the GLOBOCAN 2018 report, cancer of the stomach is the fifth most common neoplasm and the third leading cause of cancer-related mortality in the world.1 GC is divided into cardia and noncardia tumors. This cancer is also histologically classified into diffuse and intestinal types. The prognosis of GC depends on its stage: the earlier the stage at which GC is detected, the higher the possibility of curing this neoplasm. As a result, it is of utmost importance to screen and follow-up individuals at risk of developing stomach cancer.

Helicobacter pylori (H. pylori) infection is the main risk factor for GC.2 Family history, however, also plays an important role. Although hereditary GC syndromes account for only 1–3% of all cases, GC was reported to have a familial aggregation rate of up to 10%.3 Having first-degree relatives affected with GC was associated with a 2- to 10-fold increase in the risk of this bleak disease, depending on ethnicity and the region of occurrence.4

There are several hypothesized mechanisms for interpretation of familial clustering on GC, such as H. pylori infection, smoking, dietary intake, socioeconomic status, and genetic susceptibility.5 Although family history is a consistent risk for GC, no guidelines have been developed to assess the family history of individuals affected with this neoplasm. In this review, we discuss the familial aggregation of GC and a strategy of screening and surveillance for GC in individuals with a positive family history of the disease.

2 FAMILIAL AGGREGATION OF GC 2.1 Risk of GC among individuals with a family history of GC

Having first-degree relatives affected with GC was associated with an increased risk of GC.4, 6 The risk ratio was reported to be 1.5- to 3.5-fold in both low- and high-incidence areas. However, higher familial relative risks of 5.7–9.9 were reported from India (low-incidence area), Turkey (intermediate-incidence area), and Korea (high-incidence area).4 These findings might be interpreted in light of the heterogeneity of the control groups of these studies.7-9 The results from India were from a hospital-based case-control study with the control group consisting of cancer patients (all cancer sites excluding tobacco-related cancers, gastrointestinal cancers, oral cavity cancer, pharyngeal cancer, laryngeal cancer, lung cancer, pancreatic cancer, and urinary bladder cancer), which might lead to a relatively higher calculated risk of GC associated with a positive family history from this study. In a recent meta-analysis of 32 studies, the relative risk for developing GC in individuals with positive family history, including first- and second-degree relatives, was 2.35 (95% confidence interval [CI]: 1.96–2.81).6 When exclusively analyzing 26 relevant studies regarding first-degree relatives, the risk was 2.71 (95% CI: 2.08–3.53). Although the incidence of GC among the general population differs markedly according to different regions and ethnic groups, the relative risk of developing GC in individuals with first-degree family members affected with GC calculated from Asian studies was not significantly different compared to the risk among non-Asian populations (2.38 versus 2.27, respectively).6

However, the risk of developing GC is likely to be different according to which first-degree relative is affected with GC. GC risk was reported to be higher in subjects with an affected mother than an affected father (OR 2.3 and 1.3, respectively).10 Results from the study of Shin et al. were consistent with this finding, showing that the risk of GC was higher among the individuals having an affected mother rather than an affected father (OR: 3.8, 95% CI: 1.5–9.6 vs. 2.9, 95% CI 1.5–5.6).11 This study also revealed that having a sibling with GC increased the risk of GC (OR 2.4, 95% CI: 1.3–4.7), but the risk was lower than that of subjects with a parental history of GC. In contrast, several studies reported that individuals with a sibling affected with GC faced a higher risk of development of GC compared to those with a parental history of GC (OR 10.1 and 6.6, respectively).8, 9

Moreover, the number of family relatives affected with GC has been shown to be associated with an increased risk of GC. A case-control study in Italy showed that patients with two or more first-degree relatives affected with GC had a higher risk of developing GC compared to those with only one affected first-degree relative.12 A similar trend was observed in a study by Palli et al. that showed an increased risk of GC in individuals who have two or more first-degree relatives affected with the disease (OR 5.5, 95% CI: 3.0-1-0.2 vs. OR 1.7, 95% CI: 1.3–2.1).10 Another study in Korea also reported that subjects with two or more first-degree relatives affected with GC were at a higher risk of GC compared to those that had only one first-degree family member with GC (OR 9.6, 95% CI: 1.2–73.4 vs. OR 2.7, 95% CI: 1.7–4.3).11

In summary, there is consistent evidence across many countries to support that having a family history of GC is a risk factor for GC development, regardless the incidence of GC in each country. As well, the risk level of GC increases with the number of relatives affected by GC.

2.2 Mechanisms of GC with family history

The familial clustering of GC might be interpreted through several mechanisms including nonhereditary factors and genetic susceptibility.

2.2.1 H. pylori infection

In the large population-based study of Brenner et al., the prevalence of H. pylori infection was significantly higher in individuals with a parental history of GC than in those without this history (69% vs. 44%, OR 2.7, 95% CI: 1.3–5.9).13 This association was more pronounced in the younger subjects. There is a 5.1-fold higher risk of GC (OR 5.1, 95% CI: 1.6–16.1) for infected individuals with a positive history of GC compared with uninfected individuals in the young group (<50 years of age), whereas this risk in the old group is only 1.2-fold (OR 1.2, 95% CI: 0.4–3.6) and not significant. Moreover, there is a joint effect of H. pylori infection and family history on increasing the risk of developing GC of more than fivefold (OR 5.32, 95% CI: 2.76–10.25).11 In contrast, H. pylori infection without a family history of GC only showed a marginally increased risk of GC (OR 1.58, 95% CI: 0.98–2.57), and having a family history of GC without H. pylori infection did not significantly increase the risk of GC (OR 1.33, 95% CI: 0.46–3.81).11 In the meta-analysis of Rokkas et al., evaluating the relation of H. pylori infection and stomach histology in the first-degree relatives of GC patients, subjects with a family history of GC had a twofold increased rate of H. pylori infection, atrophic gastritis, and intestinal metaplasia.14 In addition, the recent randomized control trial of Choi et al. evaluated the effect of H. pylori eradication in 1838 infected subjects whose first-degree relatives were affected with GC during a median follow-up period of 9.2 years.15 The study found that H. pylori treatment reduced the risk of GC by 55% in the infected subjects with a positive family GC, and successful eradication reduced the risk by up to 73% compared to those with persistent infection. These findings suggest that familial aggregation of GC may be partly due to familial exposure to H. pylori infection.

An important question regarding the relationship between H. pylori infection and familial clustering of GC is whether there is any association between H. pylori strains and the higher risk of GC with a family history. A meta-analysis, including 44 studies, found that there was a higher risk of developing GC among individuals infected with CagA-positive H. pylori strains (OR 2.09, 95% CI: 1.48–2.94).16 However, Brenner et al. did not observe a stronger association between H. pylori infection and the risk of GC among relatives of GC patients for CagA-positive than for CagA-negative H. pylori infection.13

2.2.2 Environmental factors

Family members share environmental living conditions such as a common diet habit, exposure to smoking, and common household income. Dietary factors may partly explain the familial clustering of GC. Spicy food consumption was reported to be an independent risk factor for stomach cancer.11 Strong spicy food consumption was also a risk factor for intestinal metaplasia in the antrum among individuals without significant gastroduodenal disease.17 In addition, results from a systematic review showed that foods containing high amounts of salt and nitrites, or meat and processed meat consumption, contributed to the higher risk of GC.18 Another systematic study by Ge et al. also reported that people with high salt intake were at a 22% increased risk of developing GC.19 Red meat consumption was also reported to be a risk factor for GC, whereas white meat consumption was associated with a lower risk of GC.20

Smoking was found to be a causal risk factor for GC, with the risk increased in line with the duration and intensity of cigarette smoking.21 A recent meta-analysis also pointed to the role of alcohol consumption in the risk of GC.22 The other risk factors associated with GC were rural residency during childhood and lower monthly income.11 In contrast, an observational study reported that Epstein–Barr virus infection was more prevalent in patients with young-onset GC and suggested a role of this virus in the pathogenesis of GC.23 In their meta-analysis, Zeng et al. pointed out that human papillomavirus was a also potential risk factor for GC, with an OR of 3.314 (95% CI: 1.6-6.8).24

2.2.3 Hereditary risk factors

The association between family history and GC continued to exist after adjusting for H. pylori infection and environmental factors, which suggests the role of genetic predisposition.11 Approximately 1–3% of GC cases are hereditary syndromes. Among them, there are three main syndromes that are explained genetically, including hereditary diffuse GC, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal GC. Other hereditary syndromes include Peutz–Jeghers syndrome, juvenile polyposis syndrome, Li-Fraumeni syndrome, Lynch syndrome, hereditary breast and ovarian cancer, and familial adenomatous polyposis syndrome. The risk of GC development is relatively high (ranging from 2 to 80%) in families affected by these syndromes.25

Several proinflammatory cytokine gene polymorphisms were observed to be associated with an increased risk of GC in individuals with a family history of GC through the mechanism of enhancing the inflammatory response in gastric mucosa induced by H. pylori, such as interleukin-6 (IL-6), IL-8, IL-10, IL-1 β, tumor necrosis factor α (TNF-α), Toll-like receptor 4, and transforming growth factor β (TGF-β).26 The relationship between genetic predisposition and GC in relatives of GC patients is varied depending on regions and races: IL-1β and TNF-α genetic polymorphisms were consistently associated with GC in Caucasian patients, whereas the relation between IL-8, TGF-β polymorphisms, and GC risk were more consistent in Asian than Western populations.27

In summary, the familial aggregation of GC is associated not only with genetic susceptibility but also nonhereditary factors, especially H. pylori infection and lifestyle factors.

3 SCREENING STRATEGY FOR INDIVIDUALS WITH FAMILY HISTORY OF GC 3.1 When to start screening?

The marked variation in the incidence of GC among different countries has led to different strategies to deal with the problem. High incidence rates are found in Eastern Asia, Eastern Europe, South America, Western Asia, and Southern Europe, whereas low-incidence areas for GC include Africa, Northern America, Northern Europe, Australia, New Zealand, and South Asia.1 GC screening in the general population is recommended to begin after age 40 in Asian countries with a high prevalence of GC and after age 50 in most Western countries.28-30 In high-incidence regions, such as Korea and Japan, the incidence of GC increases sharply from the age of 40.31 In low-incidence countries, a strategy to stratify the risk of GC in their populations should be adapted based on the genetic susceptibility, epidemiologic factors, and H. pylori infection status. For individuals with a family history of GC, there has been neither consensus nor guidelines to provide clear recommendations on screening for GC in this high-risk group. The recent guidelines of the British Society of Gastroenterology (BSG) suggest endoscopic screening in subjects older than 50 years of age who have a first-degree relative with GC.28 However, the guidelines do not suggest any recommendation for screening younger individuals with such family history.

A report from the United States showed that up to 19% of GC patients younger than 40 years of age had a positive family history.32 Another study from China found a frequency of 19% among very young (<35 years old) patients with GC who reported a positive family history.33 Ławniczak et al. reported that GC patients who were younger than 40 years of age more frequently had a positive family history compared to older individuals. This study suggests that screening for GC in subjects with a positive family history should start before the age of 40.34 A retrospective study in Korea found that patients with a paternal history of GC diagnosed before 50 years of age developed GC approximately 10 years earlier than those without a family history.35 This finding suggests the necessity of earlier screening for GC among patients with such family history. The study also reported that GC occurred before the age of 40 in more than 20% of individuals with a parental history of early-onset GC but in only 7.1% of individuals without a positive family history. Thus, it is reasonable to begin screening for GC before the age of 40 in patients with a parental history of early-onset (<50 years of age) GC. This means the timing to perform upper endoscopic screening in individuals with a positive family history should be 10 years earlier than the age of GC onset in their relatives, similar to the strategy for colon cancer screening.

3.2 How to screen?

A prospective study of 1526 individuals over a follow-up period of 10 years showed that GC developed in approximately 3% of all H. pylori-infected individuals but in none of the uninfected patients.36 As there is a significant association between a family history of GC and H. pylori infection in the development of GC, screening subjects with a family history of GC and who are infected with H. pylori may be a suitable approach. There are several noninvasive tests to detect H. pylori including a serological test, 13/14C-urea breath test, and H. pylori stool antigen. Among these tests, only serology was proved to be cost-effective when considering studies on H. pylori screening for GC prevention.37 However, serology has shown low sensitivity and is not useful for detecting premalignant gastric lesions.38

Serum pepsinogens (SPG), including pepsinogen I (PGI) and pepsinogen II (PGII), and gastrin-17 are potential effective and noninvasive screening tests for GC and atrophic gastritis. A low SPG and PGI:PGII ratio and high gastrin-17 level were shown to be associated with GC and yielded good sensitivity and specificity for screening of both early and progressive GC.39 A recent meta-analysis reported that the summary sensitivity and specificity of SPG for GC screening were 0.69 (95% CI: 0.60–0.76) and 0.73 (95% CI: 0.62–0.82), respectively, whereas for atrophic gastritis screening, they were 0.69 (95% CI: 0.55–0.80) and 0.88 (95% CI: 0.77–0.94), respectively.40 Also, the combination of PGI and PGI:PGII ratio yielded a summary sensitivity and specificity of 0.70 (95% CI: 0.66–0.75) and 0.79 (95% CI: 0.79–0.80) for GC screening, whereas for atrophic gastritis, they were 0.79 (95% CI: 0.72–0.85) and 0.89 (95% CI: 0.85–0.93), respectively.40 Moreover, the combination of SPG and H. pylori serology, the so-called the ABC method, was proved to be a potential predictive marker for GC development.41 Despite its safety, cost-efficiency, and simplicity, the ABC method has not been recommended as a screening test for GC in the recent guidelines when considering the less than solid evidence of mortality reduction using this method of GC screening.42

Screening of GC among individuals with a family history of GC should be based on upper gastrointestinal endoscopic examination as endoscopy is superior to other methods in detecting precancerous gastric lesions and early GC.43 A recent study in Taiwan revealed that patients who had undergone a prior upper gastrointestinal endoscopy within 5 years before the diagnosis of GC had better survival compared to those who had never undergone an upper endoscopic exam or who had upper gastrointestinal endoscopy performed more than 5 years before the diagnosis.44 Endoscopy has been recommended as the best method and most cost-effective strategy for detecting GC in high-incidence countries such as Japan and Korea.45, 46 However, in a low-incidence country, such as the United States, endoscopy has not been recommended as the first-line technique for GC screening due to its cost-effectiveness and the limited demand for trained endoscopists in this region.38 Due to the contribution of H. pylori infection to the mechanism of GC in relatives of GC patients, in low-incidence regions, an appropriate approach to screen for GC among individuals with a family history of GC is to initially use noninvasive modalities to test for H. pylori infection and then to indicate upper gastrointestinal endoscopy for the infected patients only. However, considering the advantages of upper gastrointestinal endoscopy in the early detection of GC and reduction in mortality, there should be a change in the approach to high-risk individuals, especially those with a family history of GC in low-incidence areas. Screening for GC using upper gastrointestinal endoscopy has been found to be cost-effective when applied selectively in high-risk ethnic groups, males, smokers at the age of 50 and above, or when combined with screening colonoscopy in countries with an age-standardized rate (ASR) for GC of ≥ 10 per 100,000.47 But, there have been no studies examining the cost-effectiveness of endoscopy in screening for GC specifically among individuals with a positive family history. To implement and recommend a screening strategy for GC among individuals with only one affected family relative might burden the healthcare system. Further investigations are needed to examine the cost-effectiveness of endoscopy in screening for GC among those subjects; and whether consideration of the numbers of affected family members can have an impact on the screening strategy and the cost-effectiveness analysis.

3.3 What is the optimal screening interval?

Considering that the progression from early GC to its advanced stage was 34–44 months, as reported in previous studies, upper endoscopic screening in people with a positive family history should be performed every 2 years.48, 49 A screening interval of less than 2 years is not necessary as studies showed that patients with a family history of GC have a similar or even better prognosis than individuals without a family history.50, 51

3.4 Is H. pylori eradication needed?

In high-incidence regions, H. pylori eradication is recommended for infected individuals with a family history of GC.52 However, in low-incidence regions, such as the United States, the American College of Gastroenterology guideline in 2017 did not recommend H. pylori testing and treatment for this high-risk population because of insufficient supporting evidence.53 A recent double-blind, placebo-controlled trial in 1676 participants from South Korea with a median follow-up period of 9.2 years showed that H. pylori eradication treatment reduced the risk of GC in individuals with first-degree relatives affected with GC.15 Moreover, H. pylori eradication in infected subjects with at least a first-degree family member with GC was proved to have lower costs and produce more quality-adjusted life years compared to no eradication therapy group.54 These findings support the H. pylori eradication approach to prevent the development of GC among individuals with a positive family history. Recently, a strategy of mass H. pylori eradication for a high-risk Taiwanese population aged 30 years or older that was launched on the Matsu Islands was reported to significantly reduce the incidence of GC with the potential benefit of mortality reduction.55 These results suggest a population-based H. pylori eradication strategy, especially in regions with a high incidence of GC and high prevalence of H. pylori infection. However, wide population-based H. pylori treatment may result in antibiotic resistance and cause a negative impact on the normal intestinal microbiota, which will require long-term evaluation.

3.5 When to start H. pylori eradication?

It is thought that the earlier the eradication of H. pylori is performed, the better the patient's prognosis will be. However, one study found that up to 24% of children older than 10 years of age were reinfected with H. pylori after successful eradication, but other studies revealed that there was a low incidence of H. pylori reinfection in adults who underwent successful eradication.56-58 Moreover, early H. pylori eradication has been shown to be more cost-effective than surveillance as a cancer prevention strategy.59 The Asia-Pacific guidelines in 2008 recommended that in high-risk populations, including those with a family history of GC, H. pylori eradication should be initiated 10 to 20 years before the onset age of GC.60 This recommendation was reinforced by the evidence from a meta-analysis that the risk of GC remained after successful H. pylori eradication if atrophic gastritis and intestinal metaplasia lesions have developed to a “point of no return.”61 Another meta-analysis showed that H. pylori eradication improved atrophy of the gastric corpus but did not improve mucosa in the atrophic antrum or that in areas of gastric intestinal metaplasia.62 As a result, H. pylori eradication treatment was suggested in infected patients with atrophy of the gastric corpus. Furthermore, the severity of gastric atrophy before H. pylori eradication has been shown to be closely associated with the risk of GC after successful eradication.63 Thus, the most beneficial timing to initiate H. pylori eradication to prevent GC was before the expansion of mucosal atrophy over the lesser curvature of the stomach body.63 However, recent studies revealed that even patients with mild gastric atrophy still had an increased risk of GC development if they were followed up for a long enough time.64, 65 These findings suggest that GC risk among infected patients will be minimal if H. pylori eradication is achieved before gastric atrophy has been established. According to the Kyoto Global Consensus Report in 2015, H. pylori eradication will confer the maximum benefit if the gastric mucosa is still nonatrophic.42 But, there is no evidence to suggest the average age at which mucosa transitions from nonatrophic to atrophic in infected subjects with a family history of GC. In the study of Yeh et al., H. pylori screening and treatment at the age of 20 was shown to reduce the mean lifetime risk of GC by 14.5% in males and 26.6% in females, supporting the strategy of H. pylori eradication among younger individuals.66 However, the Yeh et al. study was based on a general population and not selective subjects with a family history of GC. The optimal timing to initiate H. pylori eradication in individuals with a family history of GC is not known. Results from a study in Iran, a country with a high prevalence of H. pylori infection, showed that precancerous lesions including those of gastric atrophy and dysplasia were found more frequently among relatives of GC patients than in those with no family history of GC despite the nonsignificant difference in the H. pylori infection rate between these two groups.67 In agreement, another study from Korea reported a higher prevalence of corpus intestinal metaplasia in GC relatives compared to controls without a family history of GC in subjects under the age of 50.68 These findings suggest earlier development of precancerous lesions of GC among this high-risk population and the effect of genetic susceptibility on GC risk. Consequently, the age of 20 (or even sooner due to the synergic effect of H. pylori infection with genetic factors) could be an appropriate time to initiate H. pylori eradication in individuals with a family history of GC. However, the optimal age for H. pylori eradication is still unknown, and this knowledge gap in the current literature needs to be investigated further.

4 SURVEILLANCE STRATEGY FOR INDIVIDUALS WITH FAMILY HISTORY OF GC

Currently, the guidelines on the management of epithelial precancerous conditions and lesions in the stomach (MAPS II) in 2019, the BSG guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma in 2019, the European Society of Gastrointestinal Endoscopy (ESGE) in 2020, and the American Society for Gastrointestinal Endoscopy (ASGE) guideline in 2015 provided recommendations regarding the surveillance strategy for individuals with a family history of GC.28, 69-71 According to the guideline of MAPS II, patients with advanced stages of atrophic gastritis (including severe atrophy and/or intestinal metaplasia affecting both antral and corpus mucosa) who have a family history of GC may benefit from a follow-up of every 1 to 2 years after diagnosis.69 For patients with intestinal metaplasia at a single location and with a family history of GC, endoscopic surveillance with chromoendoscopy and guided biopsies should be performed every 3 years.69 This guideline does not recommend endoscopy surveillance in patients with mild atrophic gastritis (atrophic mucosa limited to the antrum) but with a family history of GC. However, the guideline of the BSG in 2019 recommended that patients with gastric atrophy or gastric intestinal metaplasia limited just to the gastric antrum and with a family history of GC should be followed up every 3 years.28 The guidelines of the ASGE in 2015 and ESGE in 2020 suggest surveillance endoscopy for patients with gastric intestinal metaplasia and a family history of GC.70, 71 Nevertheless, none of the guidelines mention optimal surveillance intervals for these patients. In a recent study in a Korean population with a follow-up of 7 years, subjects with a family history of GC were more likely to have GC detected during a less than 2-year interval between a normal upper gastrointestinal endoscopy and an endoscopy confirming GC compared to those without a family history of GC (33.8% vs. 21.9%, p = .046).55 This finding suggests the interval of upper gastrointestinal endoscopy should be less than 2 years in individuals with a family history of GC, rather than 3 years as recommended in the present guidelines.

5 SCREENING AND SURVEILLANCE STRATEGY FOR HEREDITARY GC

Although hereditary GC contains multiple well-known genetic syndromes, the current published guidelines are still failing to provide clear recommendations on screening and surveillance of these disorders. The common approach for hereditary GC in the present guidelines is to initially assess a detailed family history of cancers, including the age of diagnosis and the linage for all diagnoses, then to conduct genetic testing if the clinical criteria are met, and finally to perform screening and surveillance procedures for these patients. Table 1 summarizes the updated available guidelines and literature on main hereditary GC syndromes, focusing on the criteria of testing, timing for initiating screening, screening and surveillance methods, and interval of surveillance for gastrointestinal neoplasms of these syndromes.72-75 However, as hereditary GC cases are relatively rare, the screening and surveillance strategy for hereditary GC is expected to have a low impact on the general morbidity and mortality of GC. Moreover, the low prevalence of hereditary GC and the limited availability of genetic testing services in many regions with a high incidence of GC might hinder its cost-effectiveness. As a result, the screening and surveillance strategy for hereditary GC might not significantly shape the general strategy of screening and surveillance for GC in individuals with a family history of GC.

TABLE 1. Screening and surveillance of hereditary GC Syndrome Testing criteria Starting age Screening methods Surveillance methods Interval of surveillance HDGC

≥2 GC cases in a family (first- or second-degree relatives) with one confirmed as diffuse GC

Personal history of early-onset diffuse GC (diagnosed before the age of 40)

Personal/family history (first- or second-degree relatives) of diffuse GC and lobular breast cancer with one diagnosed before the age of 50)

20, or 5 years earlier than the age of GC onset in their youngest first-degree relative CDH1 germline mutation testing and EGD with gastric biopsies - Total gastrectomy for all proven CDH1-mutation carrier - EGD if surgery is not possible 1 year FIGC

≥2 intestinal-type GC cases in a family (first- or second-degree relatives) with one diagnosed before the age of 50

 >3 intestinal-type GC cases in a family, independent of age

40, or 5 years

earlier than the age of GC onset in their youngest first-degree relative

APC gene mutation testing and EGD EGD 1 year GAPPS

Gastric polyps restricted to the stomach fundus and corpus, no evidence of duodenal and colorectal polyposis

 >100 polyps carpeting the proximal stomach, or >30 polyps in a first-degree relative

Predominantly fundic gland polyps, some having dysplasia regions

An autosomal dominant pattern of inheritance

Exclude other polyposis syndromes or PPI use.

40, or 5 years

earlier than the age of GC onset in their youngest first-degree relative

APC gene mutation testing (promoter region) and EGD EGD (surgery if polyposis cannot be managed by EGD) 1 year PJS

≥2 PJS-type polyps in the small intestine

The presence of mucocutaneous hyperpigmentation in the mouth, lips, eyes, nose, or genitalia

A family history of PJS

8 (Restarting at 18 if not detecting polyps) - STK11 germline mutation testing - EGD and colonoscopy EGD and colonoscopy - Every 2–3 years if detect polyps - Every 1–2 years when older than 50. JPS

≥3 colon juvenile polyps

Multiple juvenile polyps in the GI tract

1 polyp and family history of JPS

12-15 - BMPR1A and SMAD4 germline mutation testing - EGD and colonoscopy - EGD and colonoscopy - Colectomy and ileorectal anastomosis/proctocolectomy and ilea pouch-anal anastomosis for polyp-related symptoms and for EGC-unmanageable polyps.

1 year if detect polyps

2-3 years if not detect polyps

Li-Fraumeni syndrome Young-onset sarcoma with other tumors such as breast, brain, colorectal, and pancreatic cancer When diagnosis (colonoscopy since the age of 25) TP53 germline mutation testing - Annual whole-body MRI - CBC, LDH, ESR - Breast examination - Abdominal ultrasound - Colonoscopy

1 year

3-4 months

6 months

6 months

2-5 years

LS (gastric)

(1) Young-onset disease

(2) Family history of colorectal cancer

(3) Confirmed mismatch repair (MMR) gene mutation in family

(4) Personal/ family history of a LS-associated cancer

(5) Tumor with MSI-high or dMMR system

- Colonoscopy since the age of 20 to 25 - EGD with gastric biopsy since the age of 30 to 35

- MMR protein expression analysis by IHC and/or MSI testing by PCR

- Germline testing for MMR mutations (MLH1, MSH2, MSH6, PMS2, and/or EPCAM)

- Colonoscopy and EGD

- Colonoscopy and EGD

- Colectomy with ileorectal anastomosis for colon cancer

- Colonoscopy every 1–2 years

- EGD every 3–5 years

FAP >100 polyps in the large intestine - Colonoscopy since the age of 10 - Duodenoscopy since the age of 20–25 - APC germline mutation testing - Colonoscopy and duodenoscopy - Colonoscopy and duodenoscopy - Immediate colect

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