Hereditary nonpolyposis colorectal cancer in young colorectal cancer patients: High-risk clinic versus population-based registry

doi:10.1053/gast.2002.32537

Gastroenterology

Volume 122, Issue 4, April 2002, Pages 940-947

https://doi.org/10.1053/gast.2002.32537 Get rights and content

Abstract

Background & Aims: Early onset colorectal cancer (CRC) is an important feature of hereditary nonpolyposis colorectal cancer (HNPCC). We sought to compare rates of genetically defined HNPCC among individuals with early onset CRC drawn from a high-risk clinic and a population-based cancer registry. Methods: Probands with CRC diagnosed before 36 years of age were enrolled from a high-risk CRC clinic at the University of California, San Francisco (UCSF), and a population-based Kaiser Permanente (KP) Health Plan cancer registry. Probands provided cancer family histories and tumors for microsatellite instability (MSI) testing and MSH2/MLH1 protein immunostaining. Germline MSH2 and MLH1 mutational analysis was performed. Results: Forty-three probands were enrolled from UCSF and 23 from KP. The UCSF and KP probands had similar median age of onset of CRC (30 vs. 31 years) and the percentage with any personal or family history of another HNPCC-related cancer (70% vs. 74%). However, 28 of 40 (70%) of the UCSF tumors were MSI-H compared with 6 of 18 (33%) of KP tumors (P = 0.01), and 13 germline MSH2 or MLH1 mutations were found in the UCSF group compared with 0 in the KP group (P = 0.0001). In a multivariate analysis, institution (P = 0.002) and the total number of colorectal cancers in the family (P = 0.0001) were independent predictors of MSH2 or MLH1 mutation. Conclusions: Family history of cancer is an important feature of HNPCC, even among individuals with early onset CRC. Caution must be undertaken when extrapolating data regarding HNPCC from high-risk clinic populations to the general population.

GASTROENTEROLOGY 2002;122:940-947

Section snippets

Subjects

Probands diagnosed with CRC before the age of 36 years were recruited from 2 distinct sources, the University of California, San Francisco (UCSF) high-risk CRC clinic and the Northern California Kaiser Permanente Regional Cancer Registry. The UCSF high-risk CRC clinic has been in operation since 1996, providing genetic education, counseling, and testing to individuals that are self-referred or referred by their health care provider. The registry of Kaiser Permanente (KP) members diagnosed with

Results

A total of 66 probands with CRC diagnosed before 36 years of age were enrolled in the study, 43 from UCSF and 23 from KP. The clinical characteristics of the UCSF and KP subjects are summarized in Table 1.No significant differences were detected between the groups with respect to age of diagnosis or family history as defined by the presence of family members with CRC or any other HNPCC-related cancer. UCSF probands were slightly more likely to meet the Amsterdam or Amsterdam II criteria, but

Discussion

Detection of families with HNPCC is desirable because it will improve the efficiency of cancer prevention. However, appropriate selection of individuals for molecular testing is difficult. Published criteria for molecular testing require accurate knowledge of a patient's family history, which is often difficult to obtain. Early age of onset of CRC has long been considered a central feature of HNPCC. A diagnostic strategy for HNPCC that called for the testing of all individuals, among others,

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Cited by (30)

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines
2023, Clinical Gastroenterology and Hepatology
Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC.
After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%.
The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients.
The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.
Clinical, Pathology, Genetic, and Molecular Features of Colorectal Tumors in Adolescents and Adults 25 Years or Younger
2021, Clinical Gastroenterology and Hepatology
Colorectal cancers (CRCs) are rare in adolescents and adults ages 25 years or younger. We analyzed clinical, pathology, and molecular features of colorectal tumors from adolescents and young adults in an effort to improve genetic counseling, surveillance, and, ultimately, treatment and outcomes.
We analyzed clinical data and molecular and genetic features of colorectal tumor tissues from 139 adolescents or young adults (age, ≤25 y; median age, 23 y; 58% male), collected from 2000 through 2017; tumor tissues and clinical data were obtained from the nationwide network and registry of histopathology and cytopathology and The Netherlands Cancer Registry, respectively. DNA samples from tumors were analyzed for microsatellite instability, mutations in 56 genes, and genome-wide somatic copy number aberrations.
Mucinous and/or signet ring cell components were observed in 33% of tumor samples. A genetic tumor risk syndrome was confirmed for 39% of cases. Factors associated with shorter survival time included younger age at diagnosis, signet ring cell carcinoma, the absence of a genetic tumor risk syndrome, and diagnosis at an advanced stage of disease. Compared with colorectal tumors from patients ages 60 years or older in the Cancer Genome Atlas, higher proportions of tumors from adolescents or young adults were microsatellite stable with nearly diploid genomes, or contained somatic mutations in TP53 and POLE, whereas lower proportions contained mutations in APC.
We found clinical, molecular, and genetic features of CRCs in adolescents or young adults to differ from those of patients older than age 60 years. In 39% of patients a genetic tumor risk syndrome was identified. These findings provide insight into the pathogenesis of CRC in young patients and suggest new strategies for clinical management. Performing genetic and molecular analyses for every individual diagnosed with CRC at age 25 years or younger would aid in this optimization.
Germline Genetic Features of Young Individuals With Colorectal Cancer
2018, Gastroenterology
Citation Excerpt :
As this is a retrospective analysis of patients referred for genetic evaluation at a tertiary care academic cancer center, we acknowledge the potential for ascertainment bias. Earlier studies have reported higher prevalence of Lynch syndrome among young patients with CRC evaluated in genetics clinics as compared with other health care settings, presumably because patients with a family history of CRC are more likely to be referred for genetic evaluation.26 Indeed, we made diagnoses of Lynch syndrome in 13% of our clinic-based patients with CRC age <50, compared with 8% of those in the Ohio population-based study.29,30
The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition.
We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.
Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative.
Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.
Advances in the etiopathogenesis, identification and clinical management of hereditary and familial colorectal cancer
2011, Gastroenterologia y Hepatologia
Las formas hereditarias y familiares de cáncer colorrectal (CCR) representan aproximadamente un 30–35% de los casos de CCR. Su identificación y el correcto manejo de estas familias son fundamentales, ya que constituyen un grupo de alto riesgo de CCR que se beneficia de medidas preventivas específicas para evitar el desarrollo de esta neoplasia. Además, en algunas de estas formas de CCR, principalmente en el CCR familiar, las alteraciones responsables de la susceptibilidad genética no están bien caracterizadas, lo cual resulta prioritario para su adecuado diagnóstico y manejo. En esta revisión se discuten las novedades más importantes, presentadas en el congreso de la American Gastroenterological Association, en cuanto a etiopatogenia, identificación y manejo clínico de las formas hereditarias y familiares de CCR.
Hereditary and familial forms of colorectal cancer (CRC) represent approximately 30–35% of CRC cases. Identification of these forms and appropriate management of affected families are essential, as they constitute a group at high risk of CRC that benefits from specific preventive measures. Moreover, in some of these forms of CRC, mainly familial CRC, the alterations causing genetic susceptibility are not well characterized and thus identification of these alterations is a priority for correct diagnosis and management. The present review discusses the most important advances presented at the American Gastroenterological Association's congress on the etiopathogenesis, identification and clinical management of hereditary and familial CRC.
Underdiagnosis of Lynch Syndrome Involves More Than Family History Criteria
2010, Clinical Gastroenterology and Hepatology
Citation Excerpt :
This is especially relevant because VA users undergoing colonoscopy are mostly older than 50 years, where prevalence of Lynch syndrome is likely to be low. Another possible reason for the low referral rate for genetic counseling and testing could have been the providers' knowledge that non–family history criteria for MSI testing are less predictive of a positive genetic test for Lynch syndrome in a population with low prevalence for this syndrome.18 Nevertheless, strategies to improve recognition require further understanding of the precise cognitive errors19,20 that lead to missed Lynch syndrome diagnosis.
Physicians' cancer-related family history assessment for Lynch syndrome is often inadequate. Furthermore, the extent to which clinicians recognize non–family history–related clues for Lynch syndrome is unclear. We reviewed an integrated electronic health record (EHR) to determine diagnostic evaluation for Lynch syndrome in patients diagnosed with colorectal cancer (CRC).
We conducted a retrospective cohort study of consecutive patients with CRC, newly diagnosed at a tertiary care Veterans Affairs facility, between 1999 and 2007. A detailed review of the EHR was conducted to evaluate the presence of family history–related and non–family history–related criteria of the Bethesda guidelines. Patient outcomes (identification in clinical practice and referral for genetic testing) were also determined.
We identified a total of 499 patients (mean age, 65.4 years; 98.6% male; 51.1% non-Hispanic white). At least 1 of the Bethesda criteria was met for 57 patients (11.4%), none was met for 198 (39.7%), and there was uncertainty for 244 (48.9%) because of inadequate family history documentation and/or the patient was unsure about their family history. Forty-nine patients met criteria unrelated to family history. Only 4 of 57 patients (7%) who met the Bethesda guidelines had documentation of counseling. Among 244 patients with uncertainty, a suspicion for Lynch syndrome was documented in the EHR of 6 patients (2.5%); 3 received counseling.
Lynch syndrome is under-recognized, even when patients have clear criteria unrelated to family history. Multifaceted strategies focused on reducing providers' cognitive errors and harnessing EHR capabilities to improve recognition of Lynch syndrome are needed.
Clinics for high risk care: A new concept in the prevention of colorectal cancer
2008, Medicina Clinica

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^☆: Address requests for reprints to: Jonathan P. Terdiman, M.D., Box 1623, University of California, San Francisco, San Francisco, CA 94143. e-mail: [email protected]; fax: (415) 502-2249.

^☆☆: Supported by a Clinical Research Award from the Glaxo Wellcome Institute for Digestive Health, an American Digestive Health Foundation Outcomes Research Training Award, a grant from the Theodora Betz Foundation, the Department of Veterans Affairs Medical Research Service, a University of California, San Francisco Cancer Center Core grant, and a grant from Genzyme Corporation.

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Clinical ResearchHereditary nonpolyposis colorectal cancer in young colorectal cancer patients: High-risk clinic versus population-based registry☆,☆☆

Abstract

Section snippets

Subjects

Results

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Am J Hum Genet

Gastroenterology

Gastroenterology

Surveillance improves survival of colorectal cancer in patients with hereditary nonpolyposis colorectal cancer

Cancer Detect Prev

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer

Cancer Res

New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC

Gastroenterology

A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines

J Natl Cancer Inst

Genetic instability occurs in the majority of young patients with colorectal cancer

Nat Med

Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology

Am J Public Health

Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal cancer

JAMA

Functional significance of a novel H718Y hMLH1 alteration associated with increased colorectal cancer risk among African-Americans

Am J Hum Genet

Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer

Dis Colon Rectum

Clinical findings with implications for genetic testing in families with clustering of colorectal cancer

N Engl J Med

Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1

J Med Genet

Clinical Research
Hereditary nonpolyposis colorectal cancer in young colorectal cancer patients: High-risk clinic versus population-based registry☆,☆☆