Shilpa Grover

Prevalence and Phenotypes of APC and MUTYH Mutations in Patients With Multiple Colorectal Adenomas

CONTEXT Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. OBJECTIVES To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. MAIN OUTCOME MEASURE Prevalence of pathogenic mutations in APC and MUTYH genes. RESULTS Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. CONCLUSIONS Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.

Hereditary pancreatic cancer.

Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an estimated 43,000 new diagnoses and 36,800 deaths annually.1 The low 5-year overall survival rate of patients with pancreatic adenocarcinoma of 6% is attributable to the largely characteristically late stage of pancreatic cancer at the time of diagnosis.2 Although most cases of pancreatic adenocarcinomas are thought to be sporadic, up to 10% may be due to an underlying genetic predisposition.3–4 This article reviews the epidemiology and genetic basis of hereditary pancreatic cancer and the emerging strategies for detection of early pancreatic neoplasms in high-risk individuals.

Small intestine gastrointestinal stromal tumors.

Purpose of review To review the contemporary management of gastrointestinal stromal tumor (GIST), including endoscopy, surgery, and systemic therapy, highlighting the aspects unique to small intestinal tumors. Recent findings Tumor size, mitotic count, and site of origin are the three key prognostic factors, with mitotic count being the single strongest predictor of recurrence. Tumors arising in the small bowel have worse prognosis than those of comparable size and mitotic count arising in other organs. Endoscopy and endoscopic ultrasound-guided, fine-needle aspiration are key components in the diagnosis of GIST. The role of endoscopy in surveillance and resection remain investigational. Surgery, either open or laparoscopic, remains the only curative option, but recurrence rates are high. Adjuvant therapy with imatinib mesylate improves recurrence-free survival rates and may improve overall survival (OS) with longer duration of treatment. Neoadjuvant imatinib may play an important role in the management of patients with locally advanced disease. For patients with advanced disease, first-line imatinib and second-line sunitinib malate have improved progression-free and OS rates. Systemic treatment should be continued life-long or until treatment failure. Summary Advances in the last decade have dramatically changed the management and prognosis of patients with primary and advanced GIST.

Genetic testing in gastroenterology: Lynch syndrome.

Lynch syndrome/Hereditary non-polyposis colorectal cancer is caused by inherited germline mutations in mismatch repair (MMR) genes, and accounts for 2-5% of colorectal cancers (CRC) . It is characterized by young onset CRC and an increased risk for gynaecologic, urinary tract and gastrointestinal cancers. Family history evaluation is crucial in the early identification of individuals at risk for Lynch syndrome. Individuals whose family history includes multiple relatives with cancer, two or more primary cancers, or component tumours diagnosed at a young age, should undergo genetic evaluation for Lynch syndrome. Guidelines recommend initial evaluation of the tumour with immunohistochemistry or microsatellite instability testing followed by germline testing for mutations in MMR genes in those with abnormal results. Genetic test results can guide screening recommendations for patients and their families. However, results are not always conclusive and in such cases recommendations for cancer screening should be individualized on the basis of personal and family history.

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing

Purpose:The aim of this study was to assess whether differences in frequency and phenotype of APC and MUTYH mutations exist among racially/ethnically diverse populations.Methods:We studied 6,169 individuals with a personal and/or family history of colorectal cancer (CRC) and polyps. APC testing involved full sequencing/large rearrangement analysis (FS/LRA); MUTYH involved “panel testing” (for Y165C, G382D mutations) or FS/LRA performed by Myriad Genetics, a commercial laboratory. Subjects were identified as Caucasian, Asian, African American (AA), or other. Statistical tests included χ2, Fisher’s exact test, analysis of variance, and z approximation.Results:Among participants, 17.5% had pathogenic APC mutations and 4.8% were biallelic MUTYH carriers. With regard to race/ethnicity, 18% were non-Caucasian, with >100 adenomas and younger ages at adenoma or CRC diagnosis (P < 0.0001) than Caucasians. The overall APC mutation rate was higher in Asians, AAs, and others as compared with Caucasians (25.2, 30.9, 24, and 15.5%, respectively; P < 0.0001) but was similar in all groups when adjusted for polyp burden. More MUTYH biallelic carriers were Caucasian or other than Asian or AA (5, 7, 2.7, and 0.3%, respectively; P < 0.0001). Among Caucasians, 5% were biallelic carriers identified by panel testing versus 2% identified by sequencing/large rearrangement analysis (LRA) (P = 0.002). Among non-Caucasians, 3% undergoing panel testing were biallelic carriers versus 10% identified by sequencing/LRA (P < 0.0002).Conclusion:Non-Caucasians undergo genetic testing at more advanced stages of polyposis and/or are younger at CRC/polyp diagnosis. Restricted MUTYH analysis may miss significant numbers of biallelic carriers, particularly in non-Caucasians.Genet Med 17 10, 815–821.

Screening for Pancreatic Cancer in High-risk Populations

Pancreatic adenocarcinoma is a leading cause of cancer death. Few patients are candidates for curative resection due to the late stage at diagnosis. While most pancreatic adenocarcinomas are sporadic, approximately 10% have an underlying hereditary basis. Known genetic syndromes account for only 20% of the familial clustering of pancreatic cancer cases. The majority are due to non-syndromic aggregation of pancreatic cancer cases or familial pancreatic cancer. Screening aims to identify high-risk lesions amenable to surgical resection. However, the optimal interval for screening and the management of pancreatic cancer precursor lesions detected on imaging are controversial.

Evaluation and Surveillance Strategies for Patients at Increased Risk of Pancreatic Cancer

Pancreatic adenocarcinoma is a leading cause of cancer death due to the typical late stage at diagnosis, which results in few patients being candidates for potentially curative treatment. Although most cases of pancreatic adenocarcinomas are sporadic, 5–10 % may have an underlying hereditary basis. Family history is central to identifying individuals who have an elevated risk of pancreatic cancer and for quantifying their risk. Familial pancreatic cancer is defined as kindred with at least two first-degree relatives with pancreatic cancer. Other genetic syndromes that are associated with an increased risk of pancreatic cancer include Peutz–Jeghers syndrome, familial atypical multiple mole melanoma, hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li–Fraumeni syndrome, and hereditary pancreatitis.