Abstract
INTRODUCTION:
Risk of gastric and small intestinal cancer in Lynch syndrome (LS) remains poorly understood. We investigated the risk of gastric and small intestinal cancer in patients with LS in a large, community-based population.
METHODS:
This retrospective cohort study included all patients diagnosed with LS between January 1, 1997, and December 31, 2020, at Kaiser Permanente Northern California. Cumulative incidence of gastric cancer and small intestinal cancer was calculated using competing risk methodology.
RESULTS:
Among 1,106 patients with LS with a median follow-up of 19.3 years (interquartile range [IQR] 9.4–24.0 years), 11 developed gastric cancer (8 MSH2, 2 MLH1 and 1 PMS2) with a median diagnosis age of 56 years (IQR 42–63 years) and 11 developed small intestinal cancer (6 MSH2, 3 MLH1, 1 MSH6 and 1 PMS2) with a median diagnosis age of 57 years (IQR 50–66 years). Cumulative incidence by age 80 years was 7.26% (95% confidence internal [CI], 1.80–18.03%) for men and 3.43% (95% CI, 0.50–11.71%) for women for gastric cancer and 7.28% (95% CI, 3.19–13.63%) for men and 2.21% (95% CI, 0.23–9.19%) for women for small intestinal cancer. Pathogenic variant carriers of MSH2 and MLH1 had the highest risk of gastric and small intestinal cancer. History of Helicobacter pylori infection was associated with increased risk of gastric cancer (adjusted odds ratio 5.52; 95% CI, 1.72–17.75).
DISCUSSION:
Patients with LS, particularly MSH2 and MLH1 pathogenic variant carriers, had significantly increased lifetime risk of gastric and small intestinal cancer. Testing and treatment of H. pylori infection should be considered for all patients with LS.
KEYWORDS: Lynch syndrome, gastric cancer, small intestinal cancer, risk assessment
INTRODUCTION
Lynch syndrome (LS) is the most common inherited colorectal cancer syndrome (1). It is caused by pathogenic variants (PVs) in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) involved in the human DNA repair machinery (2). Although numerous studies have reported the benefits of intensive screening and surveillance colonoscopy in reducing colorectal cancer-related mortality in patients with LS (3), the benefits of screening for gastric cancer and small intestinal cancer in patients with LS are much less clear.
Limited data to date suggest that the cumulative incidence of gastric cancer and small intestinal cancer by age 80 years in MLH1 PV carriers is 5%–7% and 0.4%–11%, respectively; in MSH2 PV carriers, the cumulative incidence is 0.2%–9.0% for gastric cancer and 1.1%–10% for small intestinal cancer, with less available information for MSH6 and PMS2 PV carriers (4–6). Because of paucity of good quality evidence, professional society guidelines on endoscopic screening for gastric cancer and small intestinal cancer among patients with LS vary widely (4,7–9). For example, the most recent 2023 National Comprehensive Cancer Network guidelines recommend that upper endoscopy screening be performed starting at age 30–40 years and repeat every 2–4 years, preferably performed in conjunction with colonoscopy, and that push enteroscopy may be considered in place of upper endoscopy to enhance small bowel visualization although its incremental yield for neoplasia detection remains uncertain (4). By contrast, current European guidelines do not support endoscopic screening in patients with LS (10,11). Optimizing risk stratification for gastric cancer and small intestinal cancer among patients with LS will fill in an important knowledge gap and inform evidence-based endoscopic screening strategy for these patients.
In this study, we investigated the incidence of gastric and small intestinal cancer in patients with LS in a large, community-based population in the United States and compared the risk with the general population.
METHODS
Setting
This study was conducted within Kaiser Permanente Northern California (KPNC), a large integrated health system that provides comprehensive inpatient and outpatient services to over 4.5 million members in suburban, urban, and semirural regions throughout Northern California. The KPNC member population is socially, racially, and ethnically diverse and closely approximates the census demographics of the population in Northern California (12). This study was approved by the KPNC Institutional Review Board, with informed consent waived.
Study design and data ascertainment
This was a retrospective cohort study. All KPNC members diagnosed with LS who carried at least 1 PV in a MMR gene (MLH1, MSH2, MSH6, PMS2, EPCAM) between January 1, 1997, and December 31, 2020 were identified from KPNC's pathology and genetic databases. Likely PVs were included as PVs. Individuals with less than 1 year of continuous KPNC membership were excluded.
Demographic and clinical information, such as sex, age at gastric cancer or small intestinal cancer diagnosis, race and ethnicity, MMR gene germline analysis result, family history of gastric cancer, personal history of malignancies, history of Helicobacter pylori infection, and smoking history was collected from the KPNC clinical electronic database and KPNC cancer registry. The test results of H. pylori serology, stool antigen, urea breath, and rapid urease tests were obtained from the KPNC's laboratory database. The results of H. pylori testing by histopathology were obtained from KPNC's pathology database using a validated natural language processing query tool as previously described (13). Cases of gastric cancer and small intestinal cancer were identified from the KPNC's cancer registry, which meets the standards of the National Cancer Institute's Surveillance, Epidemiology, and End-Results program and identifies >98% of cancers compared with manual record review.
The 2 primary outcomes were the diagnosis of gastric cancer and diagnosis of small intestinal cancer. Study participants were followed until the earliest occurrence of the following: (i) diagnosis of gastric or small intestinal cancer. If a patient developed both gastric cancer and small intestinal cancer, the follow-up stopped after the diagnosis of the second type of cancer. (ii) December 31, 2020; (iii) death; or (iv) disenrollment of KPNC membership.
Statistical analysis
Descriptive statistics were used to describe the demographic and clinical characteristics of the study participants. The cumulative incidence rates of gastric or small intestinal cancer were calculated by decades and were reported in percentages with corresponding 95% confidence intervals (CIs). The cumulative incidence rates were derived from cumulative incidence function with death as the competing risk (Fine and Gray method) (14,15).
Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (aORs) after adjusting for sex, race and ethnicity, MMR gene, family history of gastric cancer, and history of H. pylori infection for gastric cancer and after adjusting for sex, race and ethnicity, and MMR gene for small intestinal cancer. Standardized incidence ratio (SIR) was obtained by dividing the observed number of gastric cancer or small intestinal cancer cases by the expected number of cases, as previously described (13,16). All tests were 2-sided, and a P value <0.05 was considered statistically significant. Statistical analyses were performed using SAS 9.4 (Cary, NC).
RESULTS
Between January 1, 1997, and December 31, 2020, a total of 1,106 patients were diagnosed with LS by germline analysis. Of these, 11 developed gastric cancer, 11 developed small intestinal cancer, and 1,085 did not develop either gastric or small intestinal cancer (Table 1). The median follow-up time was 19.3 years with an interquartile range (IQR) of 9.4–24.0 years.
Table 1.
Baseline characteristics of patients diagnosed with Lynch syndrome at KPNC with or without a diagnosis of gastric or small intestinal cancer
| Characteristic | Totala, n (%) | Patients with gastric cancer, n (%) | Patients with small intestinal cancer, n (%) | Patients without either cancer, n (%) |
| All | 1,106 (100.0) | 11 (100.0) | 11 (100.0) | 1,085 (100.0) |
| Age range of cancer diagnosis, yr | — | 34–79 | 47–76 | — |
| Median age at gastric or small intestinal cancer diagnosis, yr (IQR) | — | 56 (42–63) | 57 (50–66) | — |
| Sex | ||||
| Female | 729 (65.9) | 4 (36.4) | 2 (18.2) | 723 (66.6) |
| Male | 377 (34.1) | 7 (63.6) | 9 (81.8) | 362 (33.4) |
| Race and ethnicity | ||||
| Asian | 164 (14.8) | 0 | 0 | 164 (15.1) |
| Black | 33 (3.0) | 1 (9.1) | 0 | 32 (3.0) |
| Hispanic | 173 (15.6) | 4 (36.4) | 2 (18.2) | 167 (15.4) |
| Non-Hispanic White | 660 (59.7) | 6 (54.6) | 8 (72.7) | 647 (59.6) |
| Other | 76 (6.9) | 0 | 1 (9.1) | 75 (6.9) |
| MMR gene | ||||
| MLH1 | 257 (23.2) | 2 (18.2) | 3 (27.3) | 252 (23.2) |
| MSH2/EPCAM | 295 (26.7) | 8 (72.7) | 6 (54.6) | 282 (26.0) |
| MSH6 | 241 (21.8) | 0 | 1 (9.1) | 240 (22.1) |
| PMS2 | 313 (28.3) | 1 (9.1) | 1 (9.1) | 311 (28.7) |
| Family history of gastric cancer | ||||
| 1st-degree relative | ||||
| No | 1,061 (95.9) | 11 (100.0) | — | 1,041 (95.9) |
| Yes | 45 (4.1) | 0 | — | 44 (4.1) |
| 2nd-degree relative | ||||
| No | 991 (89.6) | 9 (81.8) | — | 973 (89.7) |
| Yes | 115 (10.4) | 2 (18.2) | — | 112 (10.3) |
| History of Helicobacter pylori infection | ||||
| Not tested | 550 (49.7) | 1 (9.1) | 4 (36.4) | 545 (50.2) |
| H. pylori negative | 432 (39.1) | 4 (36.4) | 5 (45.5) | 423 (39.0) |
| H. pylori positive | 124 (11.2) | 6 (54.6) | 2 (18.2) | 117 (10.8) |
| Serological methods | 52 (4.7) | 4 (36.4) | 2 (18.2) | 47 (4.3) |
| Nonserological methods | 72 (6.5) | 2 (18.2) | 0 (0.0) | 70 (6.5) |
| Smoking | ||||
| Never | 678 (61.3) | 6 (54.5) | 4 (36.4) | 668 (61.6) |
| Ever | 428 (38.7) | 5 (45.5) | 7 (63.6) | 417 (38.4) |
IQR, interquartile range; KPNC, Kaiser Permanente Northern California; MMR, mismatch repair; PVs, pathogenic variants.
One patient developed both gastric cancer and intestinal cancer. MSH2/EPCAM data included 6 patients with PVs in EPCAM, none of whom developed gastric or intestinal cancer.
Among patients who developed gastric cancer, the median age of diagnosis was 56 years (IQR 42–63 years), 63.6% (n = 7) were male, and 54.6% (n = 6) were non-Hispanic White. The percentages of patients who carried PVs in MMR genes were as follows: 72.7% (n = 8) in MSH2, 18.2% (n = 2) in MLH1, 9.1% (n = 1) in PMS2, and 0.0% (n = 0) in MSH6. In addition, 54.6% (n = 6) had a history of H. pylori infection and 45.5% (n = 5) had ever smoked tobacco (Table 1).
Among patients who developed small intestinal cancer, the median age of diagnosis was 57 years (IQR 50–66 years), 81.8% (n = 9) were male, and 72.7% (n = 8) were non-Hispanic White. The percentages of patients who carried a PV in MMR genes were as follows: 54.6% (n = 6) in MSH2, 27.3% (n = 3) in MLH1, 9.1% (n = 1) in PMS2, and 9.1% (n = 1) in MSH6. In addition, 63.6% (n = 7) had ever smoked tobacco (Table 1).
Cumulative incidence of gastric cancer and intestinal cancer
The cumulative incidence of gastric cancer increased from 0.31% (0.03%–1.66%) for men and 0.17% (0.02%–0.91%) for women by age 40 years to 7.26% (1.80%–18.03%) for men and 3.43% (0.50%–11.71%) for women by age 80 years. The cumulative incidences of small intestinal cancer increased from 0 for both men and women by age 40 years to 7.28% (3.19%–13.63%) for men and 2.21% (0.23%–9.19%) for women by age 80 years (Table 2). Cumulative incidence of gastric cancer and small intestinal cancer based on each MMR gene was summarized in Supplementary Digital Content (see Supplementary Table 3, http://links.lww.com/CTG/B162).
Table 2.
Cumulative incidence of gastric cancer and small intestinal cancer in patients with Lynch syndrome
| Age group, yr | Cumulative incidence (%)a (95% CI) | |||
| Gastric cancer | Small intestinal cancer | |||
| Male | Female | Male | Female | |
| ≤40 | 0.31 (0.03–1.66) | 0.17 (0.02–0.91) | 0.0 (0.0–0.0) | 0.0 (0.0–0.0) |
| ≤50 | 0.71 (0.14–2.39) | 0.17 (0.02–0.91) | 0.42 (0.04–2.18) | 0.21 (0.02–1.12) |
| ≤60 | 2.47 (0.90–5.47) | 0.42 (0.08–1.46) | 2.62 (0.97–5.71) | 0.21 (0.02–1.12) |
| ≤70 | 3.36 (1.31–7.05) | 0.80 (0.21–2.31) | 5.49 (2.43–10.37) | 0.21 (0.02–1.12) |
| ≤80 | 7.26 (1.80–18.03) | 3.43 (0.50–11.71) | 7.28 (3.19–13.63) | 2.21 (0.23–9.19) |
| Lifetime | 7.26 (1.80–18.03) | 3.43 (0.50–11.71) | 7.28 (3.19–13.63) | 2.21 (0.23–9.19) |
CI, confidence internal.
Derived from cumulative incidence function, with competing risk.
SIRs of gastric and small intestinal cancer compared with the general population
Compared with the KPNC general population, the SIR for gastric cancer among patients with LS was 8.06 (95% CI, 4.02–14.42) overall and 5.77 (95% CI, 1.57–14.76) for women and 10.43 (95% CI, 4.19–21.48) for men (Table 3). When stratified based on the MMR gene, the SIR was 7.74 (95% CI, 0.94–27.96) for patients with PVs in MLH1 and 23.50 (95% CI, 10.15–46.31) for patients with PVs in MSH2. SIR was not significantly elevated for PVs in MSH6 or PMS2.
Table 3.
Standardized incidence ratios of gastric cancer in patients with Lynch syndrome compared with the KPNC general population
| Variable | No. of observed cases | No. of expected cases | SIR | 95% CI |
| Total | 11 | 1.37 | 8.06 | 4.02–14.42 |
| Sex | ||||
| Female | 4 | 0.69 | 5.77 | 1.57–14.76 |
| Male | 7 | 0.67 | 10.43 | 4.19–21.48 |
| Race and ethnicity | ||||
| Racial and ethnic minoritiesa | 5 | 0.44 | 11.37 | 3.69–26.54 |
| Non-Hispanic White | 6 | 0.93 | 6.48 | 2.38–14.11 |
| MMR gene | ||||
| MLH1 | 2 | 0.26 | 7.74 | 0.94–27.96 |
| MSH2 | 8 | 0.34 | 23.50 | 10.15–46.31 |
| MSH6 | 0 | 0.33 | 0 | 0.00–9.05 |
| PMS2 | 1 | 0.44 | 2.30 | 0.06–12.79 |
CI, confidence interval; KPNC, Kaiser Permanente Northern California; MMR, mismatch repair; SIR, standardized incidence ratio.
Included people who were Asian, Black, or Hispanic.
The SIR for small intestinal cancer in patients with LS was 23.95 (95% CI, 11.95–42.85) overall and 7.43 (95% CI, 0.90–26.85) for women and 47.30 (95% CI, 21.63–89.79) for men (Table 4). When stratified by MMR gene, the SIR was 34.93 (95% CI, 7.20–102.08) for PVs in MLH1 and 53.45 (95% CI, 19.62–116.34) for PVs in MSH2. SIR was not significantly elevated for PVs in MSH6 or PMS2.
Table 4.
Standardized incidence ratios of small intestinal cancer in patients with Lynch syndrome compared with the KPNC general population
| Variable | No. of observed cases | No. of expected cases | SIR | 95% CI |
| All | 11 | 0.46 | 23.95 | 11.95–42.85 |
| Sex | ||||
| Female | 2 | 0.27 | 7.43 | 0.90–26.85 |
| Male | 9 | 0.19 | 47.30 | 21.63–89.79 |
| Race and ethnicity | ||||
| Racial and ethnic minoritiesa | 3 | 0.15 | 19.62 | 4.05–57.33 |
| Non-Hispanic White | 8 | 0.31 | 26.11 | 11.27–51.44 |
| MMR gene | ||||
| MLH1 | 3 | 0.09 | 34.93 | 7.20–102.08 |
| MSH2 | 6 | 0.11 | 53.45 | 19.62–116.34 |
| MSH6 | 1 | 0.11 | 8.84 | 0.22–49.24 |
| PMS2 | 1 | 0.15 | 6.75 | 0.17–37.63 |
CI, confidence interval; KPNC, Kaiser Permanente Northern California; MMR, mismatch repair; SIR, standardized incidence ratio.
Included people who were Asian, Black, or Hispanic.
Multivariable comparisons of the risk of gastric cancer and small intestinal cancer
History of H. pylori infection was associated with a significantly increased risk of gastric cancer (aOR 5.52, 95% CI, 1.72–17.75) compared with no H. pylori infection (Table 5). No statistically significant differences were noted by sex, race and ethnicity, or family history of gastric cancer. Additional aORs were calculated for H. pylori positivity stratified by serological and nonserological methods, but with very wide CIs due to limited number of gastric cancer cases (see Supplementary Table 4, http://links.lww.com/CTG/B162). For small intestinal cancer, female sex was associated with a significantly lower risk (aOR 0.15, 95% CI, 0.04–0.56).
Table 5.
Odds ratios of gastric cancer and small intestinal cancer in patients with Lynch syndrome
| Variable | Adjusted odds ratio | 95% CI |
| Gastric cancer | ||
| Sex | ||
| Female | 0.4 | 0.14–1.18 |
| Male (ref) | 1 | |
| Race and ethnicity | ||
| Racial and ethnic minoritiesa | 0.84 | 0.28–2.51 |
| Non-Hispanic White (ref) | 1 | |
| Any family history of gastric cancer | ||
| Yes | 1.39 | 0.37–5.23 |
| No (ref) | 1 | |
| Helicobacter pylori infection | ||
| Yes | 5.52 | 1.72–17.75 |
| No (ref) | 1 | |
| Not tested | 0.29 | 0.05–1.52 |
| Small intestinal cancer | ||
| Sex | ||
| Female | 0.15 | 0.04–0.56 |
| Male (ref) | 1 | |
| Race and ethnicity | ||
| Racial and ethnic minoritiesa | 0.56 | 0.17–1.84 |
| Non-Hispanic White (ref) | 1 |
Multivariable logistic regression analysis adjusted for sex, race and ethnicity, MMR gene, family history of gastric cancer, and history of H. pylori infection for gastric cancer and adjusted for sex, race and ethnicity, and MMR gene for small intestinal cancer.
CI, confidence interval; MMR, mismatch repair.
Included people who were Asian, Black, or Hispanic.
DISCUSSION
In this retrospective cohort study, we provided new information on the risk of gastric and small intestinal cancer among patients with LS in a large, diverse, community-based US population. Overall, our data showed that patients with LS had 8 times the risk of developing gastric cancer and 24 times the risk of developing small intestinal cancer compared with the general population. Approximately 1 in 14 men with LS developed gastric cancer and, similarly, 1 in 14 men developed small intestinal cancer by age 80 years, with lower risk in women of both cancers. Among the MMR genes, carrying a PV in MSH2 was associated with a significantly increased risk of both gastric cancer and small intestinal cancer while carrying a PV in MLH1 was associated with a significantly increased risk of small intestinal cancer and a trend toward an increased risk of gastric cancer. In addition, patients with H. pylori infection had 5.5 times the risk of developing gastric cancer compared with those without H. pylori infection.
Our data showed that the cumulative incidence of gastric cancer by age 80 years was 7.26% (95% CI, 1.80%–18.03%) for men and 3.43% (95% CI, 0.50%–11.71%) for women. When stratified by MMR gene, individuals who carried PVs in MSH2 had the highest cumulative risk of developing gastric cancer, followed by MLH1 PV carriers, while the cumulative incidence was <1% in PMS2 or MSH6 PV carriers. We did not observe any gastric cancer in MSH6 PV carriers but noted one case of gastric cancer in a 37-year-old woman who carried a PV in PMS2 (see Supplementary Table 1, http://links.lww.com/CTG/B162). These findings are overall concordant with several recent studies from different study populations (6,17,18). Data based on the Prospective Lynch Syndrome Database showed an increased gastric cancer risk in MLH1 and MSH2 PV carriers, with cumulative incidence of gastric cancer being 7.1% (3.5%–10.8%) for MLH1 and 7.7% (95% CI, 1.9%–13.6%) for MSH2 by age 75 years (17). In a recent nationwide cohort study in The Netherlands, cumulative risk of gastric cancer by age 75 years using competing risk methodology was 5% (3%–8%) for MLH1 or MSH2 PV carriers and 1% (0–2%) for MSH6 or PMS2 PV carriers (19). In a study by Ladigan-Badura et al (20) using data from the German Consortium for Familial Intestinal Cancer, 47 patients were diagnosed with gastric cancer among 1,128 patients with LS, including 21 with MLH1, 24 with MSH2, 1 with MSH6, and 0 with PMS2 PVs. Taken together, these findings underscored the heightened risk of gastric cancer in patients with LS who carry PVs in MSH2 or MLH1 and suggest possible benefits of endoscopic screening for these patients. The yield of screening MSH6 or PMS2 PV carriers seems very low although not zero. Since 16.7% of gastric cancers were diagnosed between age 30 and 39 years (see Supplementary Table 1, http://links.lww.com/CTG/B162), endoscopic screening starting between 30 and 40 years seems reasonable, although the yield and cost-effectiveness of screening should be further studied to inform the optimal starting age and interval of endoscopic screening.
With respect to small intestinal cancer, our data showed the overall cumulative incidence by age 80 years was 7.28% (95% CI, 3.19%–13.63%) for men and 2.21% (95% CI, 0.23%–9.19%) for women. PV carriers of MSH2 and MLH1 had the highest cumulative risk. Of note, among the 11 small intestinal cancer cases, 1 patient (9.1%) carried a PV in MSH6 and 1 (9.1%) carried a PV in PMS2. Similarly, PVs in MLH1 or MSH2 accounted for the majority (90.1%) of small intestinal cancers in the German Consortium study while PVs in MSH6 (3.5%) and PMS2 (4.7%) were associated with <10% of cases (21). These findings suggest that similar to gastric cancer, patients with LS who carry PVs in MSH2 or MLH1 have substantially increased cumulative risk of small intestinal cancer while the risk associated with MSH6 or PMS2 PVs is much lower but not negligible. Similar to gastric cancer, the data support possible benefits of endoscopic screening for small intestinal cancers among MSH2 and MLH1 PV carriers, but the yield of endoscopic screening for MSH6 or PMS2 PV carriers should be further investigated.
The current endoscopic options for screening of gastrointestinal cancers include standard upper endoscopy, push enteroscopy, and capsule endoscopy. Tumors located in the stomach or duodenum (proximal to the third or fourth portion) are reachable by standard upper endoscopy, but distally located small intestinal tumors need to be identified with push endoscopy, which is able to reach as far as proximal jejunum, or with capsule endoscopy, which enables the evaluation of the entire small intestine. Of the 11 small intestinal cancers in this study, 5 (45%) were located in the duodenum, 5 (45%) were located in the jejunum or ileum—of which 2 in the proximal jejunum could be reached by push enteroscopy; the location of 1 small intestinal cancer could not be clarified. Our data may suggest a potential role for push enteroscopy in diagnosing small intestinal cancer in patients with LS, but the incremental yield for routine push enteroscopy for screening beyond standard upper endoscopy seemed low and needs to be further studied (4,22,23). Regarding capsule endoscopy, a recent systematic review and meta-analysis of 5 studies with 428 patients with LS and 677 capsule endoscopies showed the overall diagnostic yield of identifying pathological confirmed lesions (adenoma or adenocarcinoma) was only 3.7% (after 2 rounds of screening) (24), with adenocarcinoma cases exclusively identified in MLH1 or MSH2 PV carriers. These findings suggested the overall very low yield of capsule endoscopy which might be improved by limiting its application to MLH1 and MSH2 PV carriers only.
One area of uncertainty is whether H. pylori plays a role in enhanced gastric cancer risk in patients with LS. A study based on a tertiary care center in the United States showed H. pylori was detected in only 2.8% of patients with LS who underwent upper endoscopy and no association between H. pylori infection and gastric cancer was noted (25). By contrast, our findings revealed 5.5 times the risk of gastric cancer in patients with LS who had a history of H. pylori infection compared with no infection. Additional analysis to stratify H. pylori positivity by using serological vs nonserological methods was limited by the small number of gastric cancer cases diagnosed. The difference in findings is likely partially related to different study populations. Our community-based study population in California has substantial race and ethnic diversity including large proportions of Hispanic, Black, and Asian individuals with a higher prevalence of H. pylori infection. Our findings support the test-and-treat strategy of H. pylori in patients with LS which is recommended by current professional society guidelines (4,10,11). Recently, Usui et al (26) reported increased risk of gastric cancer in patients with homologous recombination deficiency who also had a history of H. pylori infection. This study delineated the mechanism of increased gastric risk due to H. pylori-induced DNA damage that was unable to be successfully repaired in the setting of inherited homologous recombination deficiency (27). Although a risk increase was not observed in MMR genes likely due to insufficient sample size in that study, similar defective repair mechanism (due to MMR deficiency) may exist in patients with LS who are infected with H. pylori. Overall, it seems prudent to consider screening and treatment of H. pylori infection in all patients with LS.
Of note, although neuroendocrine tumor (NET) is not considered a typical LS-associated cancer, we identified one patient with a NET in the stomach and another patient with a NET in the duodenum (see Supplementary Table 1, http://links.lww.com/CTG/B162). There have been multiple reports of NET in the stomach, small bowel, colorectum, and pancreas in patients with LS (28–31). Further studies are needed to investigate whether there is an increased risk of gastrointestinal NETs in patients with LS.
To the best of our knowledge, this study represents the largest community-based study on the risk of gastric cancer and small intestinal cancer in patients with LS in the United States. The findings of our study should have relatively high generalizability given our diverse, community-based setting with minimal concern for selection bias. Additional strengths include long follow-up time, using competing risk methodology that provides more accurate estimates of cumulative incidence, multiple patient-level variables evaluated, and high accuracy of data extraction from a well-maintained electronic database.
There are several limitations in this study. First, the total number of gastric cancer and small intestinal cancer cases was small in our cohort despite that data were collected from a large, community-based population. This limited our ability to stratify the risk by MMR gene or by race and ethnicity. Second, although our study had a relatively long follow-up time (median follow-up 19.3 years), incident gastric or small intestinal cancers might have developed after the study participants ended their KPNC membership, which could not be ascertained. In this regard, it is possible that our results underestimated the incidence of gastric or small intestinal cancer in patients with LS. Third, because screening upper endoscopy for patients with LS were not routinely performed by all providers in our institutions, gastric or small intestinal cancer might have been underdiagnosed, although our long follow-up time might have mitigated this limitation.
In conclusion, in a large community-based US population, patients with LS had significantly increased risk of developing gastric cancer and small intestinal cancer compared with the general population. Individuals who carried PVs in MSH2 and MLH1 had the highest risk of both cancers and may benefit from endoscopic screening. The risk of gastric or small intestinal cancer associated with PVs in MSH6 and PMS2 was substantially lower, but not negligible. Our data suggest that starting endoscopic screening between 30 and 40 years may be reasonable, although the yield and cost-effectiveness of screening in different age groups and stratified by MMR genes should be further investigated. Finally, based on the strong association between H. pylori and gastric cancer risk in our LS cohort, it is reasonable to consider testing and eradication of H. pylori in all patients diagnosed with LS to reduce the risk of gastric cancer.
CONFLICTS OF INTEREST
Guarantor of the article: Dan Li, MD.
Specific author contributions: D.L.: study concept and design. All authors: acquisition of data. All authors: analysis and interpretation of data. D.L., C.L.: drafting of the manuscript. All authors: manuscript editing. All authors have approved the final draft submitted.
Financial support: This project was funded by the Graduate Medical Education supported by the Kaiser Permanente Northern California Community Health Program and by The Permanente Medical Group's Delivery Science and Applied Research Program.
Potential competing interests: None to report.
IRB approval: This study was approved by Kaiser Permanente Northern California Institutional Review Board, with informed consent waived.
Study Highlights.
WHAT IS KNOWN
✓ Patients with Lynch syndrome have an increased risk of developing gastric cancer and small intestinal cancer, but the factors affecting the cancer risk remain poorly understood.
WHAT IS NEW HERE
✓ Patients who carried pathogenic variants in MSH2 and MLH1 had the highest risk of developing gastric and intestinal cancer.
✓ In patients with Lynch syndrome, history of Helicobacter pylori infection was associated with 5.5 times the risk of developing gastric cancer compared with those without a history of H. pylori infection.
Supplementary Material
Footnotes
SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/B162
Christina F. Lin and Holly E. Carwana contributed equally to this article.
Contributor Information
Christina F. Lin, Email: clin93@gmail.com.
Holly E. Carwana, Email: Holly.E.Carwana@kp.org.
Sheng-Fang Jiang, Email: sheng-fang.jiang@kp.org.
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