Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations

Thirlwell, C; Howarth, Kimberley; Segditsas, Stefania; Guerra, Germano; Thomas, Huw; Phillips, R. K. S.; Talbot, Ian C.; Gorman, Maggie; Novelli, Marco; Sieber, Oliver M.; Tomlinson, Ian

doi:10.1038/sj.bjc.6603789

Cited by 33 publications

(25 citation statements)

References 17 publications

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“…This finding is similar to two other reports of MCRA (7, 8) with patients diagnosed at ages 50 and 60 years old. In our cohort, colorectal cancer screening guidelines appeared to influence the age of diagnosis since the majority of patients were diagnosed at screening colonoscopy.…”

Section: Discussionsupporting

confidence: 92%

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations

Tieu

Edelstein

Axilbund³

et al. 2016

Journal of Clinical Gastroenterology

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Background Patients with multiple colorectal adenomas (MCRA) without genetic cause are increasingly being diagnosed. The characteristics and natural history of this condition are not well studied. Method Twenty seven patients with MCRA, with cumulatively 10–99 colorectal adenomas and without deleterious mutations of APC or MYH genes, were investigated. Results of colonoscopies with mean follow-up of 4.9 years (range 0–27) were evaluated. Findings from esophagogastroduodenoscopy (EGD) and extracolonic manifestations were assessed. Results The mean age at polyp diagnosis and MCRA diagnosis was 47.8 ± 13.1 years (range 21–72) and 50.4 ± 14.6 years (range 21–72), respectively. In 22% of patients another family member had MCRA. At first colonoscopy, the mean number of adenomas was 35.0 ± 35.9 (range 0–99). Serrated polyps were rare. EGD revealed 47% of patients had upper tract neoplasia. Patients with upper tract findings were diagnosed with MCRA at significantly younger mean age than those without findings, p<0.05. Eighteen patients (67%) underwent colectomy with mean time from diagnosis of MCRA of 3.1 ± 1.3 years. After surgery, surveyed patients developed recurrent adenomas in retained colorectum. Nine patients (33%) had extracolonic cancers. Conclusions MCRA patients have a similar clinicopathological phenotype to known syndromes of attenuated adenomatous polyposis and the majority have need for colectomy. The management of MCRA patients and families should parallel that of attenuated FAP and MUTYH-associated polyposis (MAP) including surveillance of the upper tract.

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Section: Discussionsupporting

confidence: 92%

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations

Tieu

Edelstein

Axilbund³

et al. 2016

Journal of Clinical Gastroenterology

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“…Most efforts have focused on the identification of germline mutations that affect DNA mismatch repair genes (hMLH-1, hMSH-2, hMSH-6, hMSH-3, PMS-2), MYH/MUTYH, and APC, all of which are associated with increased numbers of colorectal adenomas and significantly increased colorectal cancer risk. 14,33,40,[44][45][46][47][48] However, our results and those of others indicate that most patients <40 years of age lack evidence of an underlying polyposis disorder and other predisposing factors. 27 The combined results of 2 reports, which evaluated 73 patients <40 years of age, found that only 4% had familial adenomatous polyposis, HNPCC, or inflammatory bowel disease, and 8% had a family history of colorectal carcinoma.…”

Section: Discussioncontrasting

confidence: 80%

Clinical, Pathologic, and Molecular Features of Early-onset Colorectal Carcinoma

Yantiss¹,

Goodarzi²,

Zhou

et al. 2009

American Journal of Surgical Pathology

154

113

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The incidence of colorectal carcinoma has increased among patients <40 years of age for unclear reasons. In this study, we describe the clinical, pathologic, and molecular features of colorectal carcinomas that developed in young patients. We compiled a study group of 24 patients <40 years of age with colorectal carcinoma, and 45 patients > or =40 years of age served as controls. Cases were evaluated for clinical risk factors of malignancy and pathologic features predictive of outcome. The tumors were immunohistochemically stained for O6-methylguanine methyltransferase, MLH-1, MSH-2, MSH-6, beta-catenin, chemokine (C-X-C motif) receptor 4, epidermal growth factor receptor, TP53, p16, survivin, and alpha-methylacyl-CoA racemase; assessed for microsatellite instability and mutations in beta-catenin, APC, EGFR, PIK3CA, KRAS, and BRAF; evaluated for micro-RNA expression (miR-21, miR-20a, miR-183, miR-192, miR-145, miR-106a, miR-181b, and miR-203); and examined for evidence of human papillomavirus infection. One study patient each had ulcerative colitis and hereditary nonpolyposis colorectal cancer. Ninety-two percent of tumors from young patients occurred in the distal colon (P=0.006), particularly the rectum (58%, P=0.02), and 75% were stage III or IV. Tumors from young patients showed more frequent lymphovascular (81%, P=0.03) and/or venous (48%, P=0.003) invasion, an infiltrative growth pattern (81%, P=0.03), and alpha-methylacyl-CoA racemase expression (83%, P=0.02) compared with controls. Carcinomas in this group showed significantly increased expression of miR-21, miR-20a, miR-145, miR-181b, and miR-203 (P< or =0.005 for all comparisons with controls). These results indicate that early-onset carcinomas commonly show pathologic features associated with aggressive behavior. Posttranslational regulation of mRNA and subsequent protein expression may be particularly important to the development of colorectal carcinomas in young patients.

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“…The clinical and family characteristics of the participants are consistent with published data from other mutation-negative polyposis cohorts. 14; 15; 19; 55 Using this approach, we identified two families with biallelic LoF germline mutations in the MMR gene MSH3, a genotype which has not yet been described as causative for a polyposis phenotype. In addition, we found one individual with biallelic PMS2 mutations, and several persons who harbored homo- and heterozygous LoF variants.…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Adam

Spier

Zhao

et al. 2016

The American Journal of Human Genetics

209

161

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In around 30% of families with colorectal adenomatous polyposis, no germline mutation in the previously-implicated genes APC, MUTYH, POLE, POLD1, or NTHL1 can be identified, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis was performed. We identified two unrelated individuals with differing compound-heterozygous loss-of-function germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1g>a, c.2760delC, c.3001-2a>c) was indicated on RNA and protein level. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST) and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the loss-of-function effect and causal relevance of the mutations. The pedigrees, genotypes, and the frequency of MSH3 mutations in the general population are consistent with an autosomal recessive mode of inheritance. Both index persons had an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study we describe biallelic germline mutations of MSH3 in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

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Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations

Cited by 33 publications

References 17 publications

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations

Clinical, Pathologic, and Molecular Features of Early-onset Colorectal Carcinoma

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

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