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

Terdiman, Jonathan P.; Levin, Theodore R.; Allen, Brian; Gum, James R.; Fishbach, A.; Conrad, Peggy; Miller, Glenn A.; Weinberg, Vivian; Bachman, Ronald; Bergoffen, JoAnn; Stembridge, Ann; Toribara, Neil W.; Sleisenger, Marvin H.; Kim, Young S.

doi:10.1053/gast.2002.32537

Cited by 29 publications

(22 citation statements)

References 27 publications

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“…In contrast, among the population based registry, only 33% of the tumours had high frequency microsatellite instability and no germline MLH1 and MSH2 mutations were identified. 23 In our series, colorectal cancer was seen in a parent of the affected child in seven of 16 families, with age of first diagnosis in the parent ranging from 20 to 63 years. Current colorectal screening recommendations include surveillance colonoscopy starting 10 years prior to the age of the youngest first degree relative diagnosed with colorectal carcinoma.…”

Section: Discussionmentioning

confidence: 58%

“…Terdiman et al compared rates of genetically defined HNPCC among individuals with colorectal cancer diagnosed before 36 years of age who were identified at a high risk clinic in California (median age 30 years; range [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and at a population based cancer registry (median age 31 years; range 14-35). Seventy per cent of tumours in 40 subjects had high frequency microsatellite instability and 30% had germline MLH1 and MSH2 mutations.…”

Section: Discussionmentioning

confidence: 99%

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Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma

Durno¹

2005

Gut

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Background: Colorectal cancer is extremely rare in childhood. Published case series reporting children and adolescents with colorectal cancer have not focused on the underlying genetic aspects of the tumour or genetic susceptibility of the families. Aims: We examined a cohort of patients with early onset colorectal cancer to determine whether a specific genetic predisposition could be elucidated. In particular, we focused on whether DNA mismatch repair gene deficiency which causes hereditary non-polyposis colorectal cancer (HNPCC) could be elucidated. Methods: Patients with colorectal cancer (24 years of age were identified from a database at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital, Toronto. Detailed pedigrees were ascertained from the proband or parents. Tumours were tested for microsatellite instability, a hallmark of HNPCC. Germline mismatch repair gene mutations (MSH2 and MLH1) were sought in some cases. Clinical data were obtained by chart audit. Results: Among 1382 probands in our registry, 16 (1%) colorectal cancer patients were 24 years or younger at the time of diagnosis. Microsatellite instability was identified in tumours from eight (73%) of 11 evaluated patients. Germline mutations in mismatch repair genes were identified in six of 12 patients, including MSH2 (n = 3), MLH1 (n = 2), and PMS2 (n = 1). Ten (63%) of 16 families met the Amsterdam criteria for HNPCC. Among these, six were screened for mismatch repair gene mutations and three were found to carry MSH2 or MLH1 germline mutations. Location of the colorectal cancers included rectum/ sigmoid (n = 9), splenic flexure (n = 2), hepatic flexure (n = 3), and caecum (n = 2). Forty four per cent (7/ 16) of these young cases developed additional malignancies (gastrointestinal (n = 8) and extraintestinal (n = 4)) during follow up (mean 12.8 (SD 12.4) years (range 0.08-30)). Conclusions: Patients with early onset colorectal carcinoma often have an inherited predisposition to the disease. Tumours with high frequency microsatellite instability and germline mutations of mismatch repair genes are sufficiently common in this patient population that they should be considered, even though family histories may not satisfy the stringent Amsterdam criteria for HNPCC. Young colorectal cancer patients are at increased risk of developing second gastrointestinal and extraintestinal malignancies.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma

Durno¹

2005

Gut

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“…Second, the methods used to assess the MSI status are highly heterogeneous, and the proteins analyzed by immunohistochemistry are usually restricted to MLH1 and MSH2. Finally, the majority of studies have analyzed either high-risk or general populations of CRC, and it is known that the rate of MSI is much lower in the latter (29). Our study, based on a large unselected population of CRC ≤50 years, shows that the overall frequency of MMR deficiency in this population is ~15%.…”

Section: Discussionmentioning

confidence: 99%

MSH6 and MUTYH Deficiency Is a Frequent Event in Early-Onset Colorectal Cancer

Giraldez

Balaguer

Bujanda

et al. 2010

Clinical Cancer Research

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Purpose: Early-onset colorectal cancer (CRC) is suggestive of a hereditary predisposition. Lynch syndrome is the most frequent CRC hereditary cause. The MUTYH gene has also been related to hereditary CRC. A systematic characterization of these two diseases has not been reported previously in this population.Experimental Design: We studied a retrospectively collected series of 140 patients ≤50 years old diagnosed with nonpolyposis CRC. Demographic, clinical, and familial features were obtained. Mismatch repair (MMR) deficiency was determined by microsatellite instability (MSI) analysis, and immunostaining for MLH1, MSH2, MSH6, and PMS2 proteins. Germline MMR mutations were evaluated in all MMRdeficient cases. Tumor samples with loss of MLH1 or MSH2 protein expression were analyzed for somatic methylation. Germline MUTYH mutations were evaluated in all cases. BRAF V600E and KRAS somatic mutational status was also determined.Results: Fifteen tumors (11.4%) were MSI, and 20 (14.3%) showed loss of protein expression (7 for MLH1/PMS2, 2 for isolated MLH1, 3 for MSH2/MSH6, 7 for isolated MSH6, and 1 for MSH6/PMS2). We identified 11 (7.8%) germline MMR mutations, 4 in MLH1, 1 in MSH2, and 6 in MSH6. Methylation analysis revealed one case with somatic MLH1 methylation. Biallelic MUTYH mutations were detected in four (2.8%) cases. KRAS and BRAF V600E mutations were present in 39 (27.9%) and 5 (3.6%) cases, respectively.Conclusions: Loss of MSH6 expression is the predominant cause of MMR deficiency in early-onset CRC. Our findings prompt the inclusion of MSH6 and MUTYH screening as part of the genetic counseling of these patients and their relatives. Clin Cancer Res; 16(22); 5402-13. ©2010 AACR.

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“…This is especially relevant in that 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 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.…”

Section: Discussionmentioning

confidence: 99%