One to 2-Year Surveillance Intervals Reduce Risk of Colorectal Cancer in Families With Lynch Syndrome

doi:10.1053/j.gastro.2010.02.053

Gastroenterology

Volume 138, Issue 7, June 2010, Pages 2300-2306

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https://doi.org/10.1053/j.gastro.2010.02.053 Get rights and content

Background & Aims

Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%–3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program.

Methods

The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy.

Results

After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without.

Conclusions

With surveillance intervals of 1–2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2–3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended.

Section snippets

Dutch Lynch Syndrome Registry

In 1987, a national registry for families with hereditary CRC was established in The Netherlands. The registry had three objectives: (1) to promote surveillance in families at risk for CRC; (2) to guarantee the continuity of the surveillance program; and (3) to promote research in the field. The methods and approach of the registry have been described elsewhere.¹⁰ In brief, clinical specialists or clinical genetics centers from all parts of The Netherlands refer to the registry as any family

Surveillance of Lynch Syndrome Families

A total of 745 MMR mutation carriers (male 308) were included. The characteristics of this study group are shown in Table 1. The carriers belong to 205 families with a pathogenic MMR mutation. Seventy-five of the families harbored an MLH1 mutation, 87 an MSH2 mutation, and 43 an MSH6 mutation.

The mean follow-up was 7.2 years (range, 0.4–13.7 years). The mean surveillance interval was 16 months. Thirty-three patients (4.4%) developed CRC under surveillance. The age at diagnosis of CRC in these

Discussion

The present study demonstrates that carriers of an MMR gene mutation have a relatively low risk of developing CRC with 2 years' surveillance intervals. Although the risk of CRC was substantially higher in carriers ≥40 years of age compared with carriers <40 years and the risk was higher in carriers of MLH1 and MSH2 mutations compared with carriers of MSH6 mutations, the differences were only of borderline significance. Relatives of non-LS families have a significantly lower risk of developing

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Cited by (197)

Lynch syndrome (hereditary nonpolyposis colon cancer). Nonsyndromic familial colon cancer
2024, Medicine (Spain)
El síndrome de Lynch es el síndrome hereditario de cáncer colorrectal (CCR) más común, siendo respon-sable de un 2%-4% de todos los casos de CCR a nivel global. Sigue un patrón de herencia autosómico dominante y se define por la presencia de una variante patogénica en línea germinal de alguno de los genes que codifican para las proteínas reparadoras del ADN (MMR), MLH1, MSH2, MSH6, PMS2, o en el extremo 3’ del gen EPCAM. Este síndrome condiciona un mayor riesgo de desarrollar CCR y cáncer de endometrio, además de otros tumores. Su diagnóstico se basa en criterios clínicos que tienen en cuenta los antecedentes familiares y personales de tumores, la detección de un fenotipo deficitario para MMR en el tejido tumoral y en el estudio genético en línea germinal de los individuos con riesgo de presentarlo. Su diagnóstico precoz permite establecer estrategias de cribado de cara a intentar prevenir o detectar la presencia de tumores en fases precoces que, en el caso del CCR, han demostrado aumentar la supervivencia. En el CCR familiar no sindrómico se incluyen aquellos casos que presentan un componente familiar sin un mecanismo molecular bien establecido, y que se pueden beneficiar de un seguimiento más intensivo que el que se establece en la población general.
Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. It accounts for 2% to 4% of all CRC cases globally. It follows an autosomal dominant inheritance pattern and is defined by the presence of a pathogenic germline variant of one of the genes that encodes for DNA repair proteins (MMR), MLH1, MSH2, MSH6, PMS2, or at the 3’ end of the EPCAM gene. This syndrome entails a greater risk of developing CRC and endometrial cancer, in addition to other tumors. Its diagnosis is based on clinical criteria that take into account the family and personal history of cancer, the detection of a deficient MMR phenotype in the tumor tissue, and a genetic study of the germline of individuals at risk of having it. Its early diagnosis allows for establishing screening strategies to try to prevent or detect the presence of tumors in early stages which, in the case of CRC, has been shown to increase survival. Nonsyndromic familial CRC includes cases that have a familial component without a well-established molecular mechanism. They may benefit from more intensive follow-up than what is established for the general population.
Incidence and prevalence of advanced colorectal neoplasia in Lynch syndrome
2023, Gastrointestinal Endoscopy
Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Although colonoscopy reduces CRC in LS, the protection is variable. We assessed the prevalence and incidence of neoplasia in LS during surveillance colonoscopy in the United States and factors associated with advanced neoplasia.
Patients with LS undergoing ≥1 surveillance colonoscopy and with no personal history of invasive CRC or colorectal surgery were included. Prevalent and incident neoplasia was defined as occurring <6 months before and ≥6 months after germline diagnosis of LS, respectively. We assessed advanced adenoma (AA), CRC, and the impact of mismatch repair pathogenic variant (PV) and typical LS cancer history (personal history of EC and/or family history of EC/CRC) on outcome.
A total of 132 patients (inclusive of 112 undergoing prevalent and incident surveillance) were included. The median examination interval and duration of prevalent and incident surveillance was .88 and 1.06 years and 3.1 and 4.6 years, respectively. Prevalent and incident AA were detected in 10.7% and 6.1% and invasive CRC in 0% and 2.3% of patients. All incident CRC occurred in MSH2 and MLH1 PV carriers and only 1 (.7%) while under surveillance in our center. AAs were detected in both LS cancer history cohorts and represented in all PVs.
In a U.S. cohort of LS, advanced neoplasia rarely occurred over annual surveillance. CRC was diagnosed only in MSH2/MLH1 PV carriers. AAs occurred regardless of PV or LS cancer history. Prospective studies are warranted to confirm our findings.
The predicted effect and cost-effectiveness of tailoring colonoscopic surveillance according to mismatch repair gene in patients with Lynch syndrome
2022, Genetics in Medicine
Lynch syndrome-related colorectal cancer (CRC) risk substantially varies by mismatch repair (MMR) gene. We evaluated the health impact and cost-effectiveness of MMR gene-tailored colonoscopic surveillance.
We first estimated sex- and MMR gene-specific cumulative lifetime risk of first CRC without colonoscopic surveillance using an optimization algorithm. Next, we harnessed these risk estimates in a microsimulation model, “Policy1-Lynch,” and compared 126 colonoscopic surveillance strategies against no surveillance.
The most cost-effective strategy was 3-yearly surveillance from age 25 to 70 years (pathogenic variants [path_] in MLH1 [path_MLH1], path_MSH2) with delayed surveillance for path_MSH6 (age 30-70 years) and path_PMS2 (age 35-70 years) heterozygotes (incremental cost-effectiveness ratio = Australian dollars (A) $8,833/life-year saved). This strategy averted 60 CRC deaths (153 colonoscopies per death averted) over the lifetime of 1000 confirmed patients with Lynch syndrome (vs no surveillance). This also reduced colonoscopies by 5% without substantial change in health outcomes (vs nontailored 3-yearly surveillance from 25-70 years). Generally, starting surveillance at age 25 (vs 20) years was more cost-effective with minimal effect on life-years saved and starting 5 to 10 years later for path_MSH6 and path_PMS2 heterozygotes (vs path_MLH1 and path_MSH2) further improved cost-effectiveness. Surveillance end age (70/75/80 years) had a minor effect. Three-yearly surveillance strategies were more cost-effective (vs 1 or 2-yearly) but prevented 3 fewer CRC deaths.
MMR gene-specific colonoscopic surveillance would be effective and cost-effective.
Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome
2022, Genetics in Medicine
This study aimed to characterize MSH6/PMS2-associated mismatch repair–deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes.
Patients who consented to Institutional Review Board–approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests.
We identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years.
MSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines.
Experiences of living with Lynch Syndrome: A reflexive thematic analysis
2022, European Journal of Oncology Nursing
Lynch Syndrome is one of the most common hereditary cancer syndromes, arising from DNA mismatch repair. Lynch Syndrome carriers are at increased lifetime risk of developing certain cancers, such as colorectal and endometrial. This increased risk can result in adverse psychological outcomes. The present qualitative study explores the experiences of individuals with Lynch Syndrome when accessing and managing healthcare in the period after learning of their Lynch Syndrome status.
Twelve interviews were conducted with Lynch Syndrome carriers in Ireland, with recruitment occurring predominantly online through closed social media platforms. This was coordinated by Lynch Syndrome Ireland, a patient representative group. Reflexive thematic analysis was used to analyse the data. There was significant Public and Patient Involvement in this study, with the committee members (N = 2) of Lynch Syndrome Ireland acting on the panel. The involvement of the PPI panel began from initial project idea conception and continued throughout the study.
Lynch Syndrome carriers highlighted the lack of adequate information from medical professionals regarding their diagnosis. Furthermore, participants spoke of the significant lack of knowledge amongst medical professionals about Lynch Syndrome. A theme depicting guilt was also noted regarding passing Lynch Syndrome to their children, and the worry experienced when children underwent genetic testing.
This study highlighted the experiences of having a Lynch Syndrome diagnosis and demonstrates a need for further psychological and medical support for the Lynch Syndrome community, including a clear need for improvements in genetic cancer services in this field.
Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome
2022, Clinical Gastroenterology and Hepatology
Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS.
We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model.
The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%–65.2%) and 7.9% (95% CI, 5.2%–10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06–4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15–3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14–0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03–1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17–3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02–2.33).
Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

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: Conflicts of interest The authors disclose no conflicts.

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Clinical—Alimentary TractOne to 2-Year Surveillance Intervals Reduce Risk of Colorectal Cancer in Families With Lynch Syndrome

Background & Aims

Methods

Results

Conclusions

Section snippets

Dutch Lynch Syndrome Registry

Surveillance of Lynch Syndrome Families

Discussion

Lancet Oncol

Gastroenterology

Gastroenterology

Lancet

Am J Med

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Clinical—Alimentary Tract
One to 2-Year Surveillance Intervals Reduce Risk of Colorectal Cancer in Families With Lynch Syndrome