Cancer Risk in Families Fulfilling the Amsterdam Criteria for Lynch Syndrome

Question  What are the cancer risks in members of families meeting the Amsterdam criteria for Lynch syndrome?

Findings  In a population-based study, all Amsterdam criteria–positive pedigrees in Utah were ascertained and 202 families with 443 colorectal cancers that accounted for 2.6% of all colorectal cancer in the state were identified. Cancers observed in significant excess in the first-degree relatives of Amsterdam criteria pedigrees included colorectal, endometrial, stomach, small intestine, prostate, kidney, and bladder cancer, as well as non-Hodgkin lymphoma; the risk of colorectal and endometrial cancers was also found to be elevated in second-degree and first-cousin relatives of families with Amsterdam criteria.

Meaning  This study provides clinicians with population-based, unbiased data to counsel members of families with Amsterdam criteria regarding their elevated risks of cancer and the importance of cancer screening.

Importance  The data describing cancer risks associated with Lynch syndrome are variable.

Objectives  To quantify the prevalence of families that fulfill the Amsterdam I or II criteria for Lynch syndrome in the Utah population and investigate the risk of colonic and extracolonic cancers in family members and their relatives.

Design, Setting, and Participants  In a population-based study, 202 families with Amsterdam I and II criteria–positive pedigrees in the Utah Population Database were identified. Of these, all cancer diagnoses in members of families with Amsterdam criteria and their first-degree, second-degree, and first-cousin relatives were located through linkage to the Utah Cancer Registry. The study was conducted from May 1 to June 30, 2016.

Main Outcomes and Measures  Standardized morbidity ratios (SMRs) were estimated by comparing the observed rates of cancer in relatives with population-expected rates estimated internally from the Utah Population Database.

Results  A total of 202 families meeting Amsterdam criteria for Lynch syndrome accounted for 2.6% of all colorectal cancers in the state; of these, 59 met both the Amsterdam I and Amsterdam II criteria. Cancers observed in significant excess in the first-degree relatives of Amsterdam criteria pedigrees included colorectal (SMR, 10.10; 95% CI, 9.43-10.81), endometrial (SMR, 5.89; 95% CI, 5.09-6.78), stomach (SMR, 2.90; 95% CI, 2.02-4.03), small intestine (SMR, 7.72; 95% CI, 5.17-11.08), prostate (SMR, 1.94; 95% CI, 1.73-2.17), kidney (SMR, 3.22; 95% CI, 2.45-4.16), urinary bladder (SMR, 1.62; 95% CI, 1.22-2.12), thyroid (SMR, 2.26; 95% CI, 1.55-3.17), and non-Hodgkin lymphoma (SMR, 2.10; 95% CI, 1.64-2.65). Risks of colorectal and endometrial cancers were also found to be elevated in second-degree (SMR, 4.31; 95% CI, 3.98-4.65 and SMR, 2.70; 95% CI, 2.30-3.14, respectively) and first-cousin (SMR, 1.85; 95% CI, 1.70-2.00 and SMR, 1.50; 95% CI, 1.29-1.73, respectively) relatives of families with Amsterdam criteria.

Conclusions and Relevance  In this population-based study of cancer risk in families fulfilling the Amsterdam criteria, many of the cancers previously reported to be associated with Lynch syndrome were observed, several previously unreported cancer associations were noted, and the risk of colorectal and endometrial cancer were markedly increased in first-, second-, and even third-degree relatives of these families. This study provides clinicians with population-based, unbiased data to counsel members of families meeting the Amsterdam criteria regarding their elevated risks of cancer and the importance of cancer screening.

Colorectal cancer (CRC) is the fourth most common cancer in the United States and is the second leading cause of cancer-related mortality.¹ Heritability is 1 of the strongest risk factors for CRC and familial clustering of CRC accounts for 25% to 30% of CRC.²

Lynch syndrome is an autosomal-dominant syndrome that accounts for up to 5% of CRC and is characterized by as much as an 80% lifetime risk of CRC and several extracolonic cancers. Lynch syndrome has been associated with germ-line mutations in the MSH2, MLH1, MSH6, PMS2, or EPCAM genes.^3,4

Because families with Lynch syndrome have a markedly increased risk of CRC and screening can reduce morbidity and mortality in these individuals, several clinical criteria have been proposed to identify Lynch syndrome.⁵ The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer defined the Amsterdam I and II criteria that are widely used to identify patients and families at risk for Lynch syndrome.^6,7 Several studies that have evaluated cancer risk associated with Lynch syndrome^8-11 have been limited by selection bias, insufficient confirmation of cancer diagnosis in relatives, and lack of reliable population-based controls.

In the present study, we used the Utah Population Database (UPDB; http://healthcare.utah.edu/huntsmancancerinstitute/research/updb/), a unique resource linking genealogy and cancer data for the state, to identify families classified by Amsterdam criteria in an unbiased manner. The objective was to investigate cancer risks in patients and their relatives from families that meet Amsterdam criteria and are at risk for Lynch syndrome.

We performed a retrospective, population-based, case-control study of cancers diagnosed in Utah between 1966 and 2013 and recorded in the Utah Cancer Registry (UCR) merged with UPDB genealogies to investigate the familial aggregation of cancers. The UPDB combines genealogies from the Genealogical Society of Utah, dating back to the early 1800s, and includes nearly 8 million individuals. The UCR is a statewide cancer registry established in 1966 and, since 1973, it has been part of the Surveillance, Epidemiology, and End Results Program network of the National Cancer Institute registries. By state law, all incident cancer diagnoses must be reported to the UCR.

This study was approved by the institutional review boards of the University of Utah, Intermountain Healthcare, and the Resource for Genetic and Epidemiologic Research. Data are deidentified.

Within the set of 17 087 CRC cases records from UCR during 1966-2013, we identified all clusters of CRC cases that matched the Amsterdam I or II criteria, described in eTable 1 in the Supplement. Only individuals who were members of families with at least 4 generations were considered in the present study. Patients who had a diagnosis of familial adenomatous polyposis (confirmed APC mutation) in our institution’s hereditary gastrointestinal cancer registry, which cares for most such families in Utah, were excluded from the study population.

Familial risk was measured using standardized morbidity ratios (SMRs) or relative risk. The SMRs in relatives, using age- and sex-matched cancer rates, were estimated from the UPDB and are detailed in the eMethods of the Supplement.¹²

Fifty-nine families fulfilled the Amsterdam I criteria and 202 families (including the 59 with Amsterdam I criteria) fulfilled the Amsterdam II criteria (eTable 2 in the Supplement). Among the 17 087 patients in the Utah population affected by colorectal cancer, 443 (2.6%) of the cases were members of the families that fulfilled the Amsterdam criteria.

We analyzed the risk of extracolonic cancers in the proband cancer cases in the families that fulfilled the Amsterdam I or II criteria (Table 1 and Table 2). Proband cases who were members of Amsterdam I criteria families were at increased risk for endometrial cancer (SMR, 6.14; 95% CI, 2.25-13.37). Proband members of the Amsterdam II criteria families were at increased risk for multiple cancer sites, including melanoma (SMR, 1.99; 95% CI, 1.06-3.40), ovary (SMR, 22.92; 95% CI, 17.12-30.06), prostate (SMR, 1.96; 95% CI, 1.35-2.75), kidney (SMR, 7.57; 95% CI, 4.33-12.29) and brain (SMR, 51.13; 95% CI, 39.46-65.17).

We also analyzed the cancer risk in the first-, second-, and third-degree relatives of the proband cancer cases in the families meeting the Amsterdam I and II criteria. First-degree relatives of the Amsterdam II criteria proband cases showed increased risks for colorectal (SMR, 10.10; 95% CI, 9.43-10.81), endometrial (SMR, 5.89; 95% CI, 5.09-6.78), stomach (SMR, 2.90; 95% CI, 2.02-4.03), and small intestine (SMR, 7.72; 95% CI, 5.17-11.08) cancer. Colorectal and endometrial cancers were elevated in both second-degree relatives (SMR, 4.31; 95% CI, 3.98-4.65 for CRC and SMR, 2.70; 95% CI, 2.30-3.14 for endometrial cancer) and first cousins (SMR, 1.85; 95% CI, 1.70-2.00 for CRC and SMR, 1.50, 95% CI, 1.29-1.73 for endometrial cancer). Similar elevated cancer risks were found for relatives of families meeting Amsterdam I criteria.

The present study classified the Utah population according to the Amsterdam I and II criteria and found that 2.6% of all CRCs in the state occurred in these families, consistent with findings that Lynch syndrome accounts for 1% to 4% of CRCs.¹³ Physicians often need to counsel patients or their relatives from families fulfilling the Amsterdam criteria on cancer risk without the benefit of a clear genetic diagnosis. The results of this study shed light on the cancers for which members of the families meeting Amsterdam I and II criteria and their relatives are at increased risk and are in overall agreement with findings from a Swedish study of similar families.¹⁴ Although clinicians likely counsel first-degree relatives of members of families that fulfill the Amsterdam criteria to initiate earlier and more frequent colorectal cancer screening, they likely do not provide a similar recommendation to more distant relatives of cancer cases in these families. Our results suggest that second-degree relatives of patients with cancer in families meeting the Amsterdam criteria are at a markedly increased risk (4.3-fold) of CRC and should be counseled for more intensive screening, similar to what is offered for those with an isolated family history of CRC.¹⁵

In addition to the commonly affected cancer sites in Lynch syndrome, our study suggested an increased risk of several extracolonic rare cancers, which is in agreement with other studies.^8,9,11,14 This information for nontypical cancers may add to the clinical criteria for Lynch syndrome.

Our study has several strengths. We took advantage of the unique linkage of the UPDB to UCR to confirm cancer diagnosis and familial relationships spanning multiple generations without ascertainment, referral, or recall bias. The ability to exclude patients with familial adenomatous polyposis in this study has likely reduced bias in terms of cancer risk assessment in families with multiple generations of CRC. The present study also has limitations. Affiliation with the Church of Jesus Christ of Latter-day Saints is associated with low rates of smoking and alcohol use in this population and could also differ from other populations; in addition, other hereditary cancer syndromes could not be excluded.

We found that 2.6% of CRC cases in Utah fulfilled the Amsterdam criteria and that CRC and endometrial cancer should be the focus of clinical counseling in these families. In addition, we found that a number of other rarely noted sites appear to be observed in excess in these families and second-degree relatives of probands in families meeting Amsterdam criteria are at markedly increased risk of CRC and should be counseled to initiate colorectal screening at an earlier age and a shorter surveillance interval. This study provides clinicians with population-based, unbiased data to counsel members of Amsterdam criteria families regarding their elevated risks of cancer and the importance of cancer screening.

Accepted for Publication: February 21, 2017.

Corresponding Author: N. Jewel Samadder, MD, MSc, Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85255 (nsamadde@gmail.com).

Published Online: August 3, 2017. doi:10.1001/jamaoncol.2017.0769

Author Contributions: Drs Samadder and Curtin full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Samadder, Smith, Hanson, Kopituch, Burt, Curtin.

Acquisition, analysis, or interpretation of data: Samadder, Wong, Thomas, Hanson, Boucher, Cannon-Albright, Curtin.

Drafting of the manuscript: Samadder, Boucher, Curtin.

Critical revision of the manuscript for important intellectual content: Samadder, Smith, Wong, Thomas, Hanson, Kopituch, Cannon-Albright, Burt.

Statistical analysis: Smith, Wong, Thomas, Boucher, Curtin.

Obtained funding: Samadder.

Administrative, technical, or material support: Samadder, Kopituch, Burt.

Supervision: Samadder, Smith, Cannon-Albright, Burt.

Conflict of Interest Disclosures: Dr Samadder is a paid consultant for Cook Medical and Covidien Medical. No other conflicts were disclosed.

Funding/Support: Support for this project was provided by National Cancer Institute grants P01-CA073992 and R01-CA040641 (Dr Burt), an Endoscopic Research Award from the American Society for Gastrointestinal Endoscopy (Dr Samadder), and a Junior Faculty Career Development Award from the American College of Gastroenterology (Dr Samadder). Partial support for the Utah Population Database and this project was provided by the Huntsman Cancer Institute Cancer Center Support grant P30CA042014 from the National Cancer Institute and the Huntsman Cancer Foundation. Support for the Utah Cancer Registry is provided by Contract HHSN 261201000026C from the National Cancer Institute with additional support from the Utah Department of Health and the University of Utah.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.