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IMPORTANCE Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. OBJECTIVE To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. DESIGN, SETTING, AND PARTICIPANTS Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. MAIN OUTCOMES AND MEASURES Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. RESULTS In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. CONCLUSIONS AND RELEVANCE Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Purpose: We investigated the contribution of Sonic hedgehog (SHH) to pancreatic cancer progression. Experimental Design: We expressed SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), and evaluated the effects on tumor growth.We also directly inhibited the activity of SHH in vivo by administering a blocking antibody to mice challenged orthotopically with the Capan-2 pancreatic cancer cell line, which is known to express SHH and form moderately differentiated tumors in nude mice. Results: Our data provide evidence that expression of SHH influences tumor growth by contributing to the formation of desmoplasia in pancreatic cancer. We further show that SHH affects the differentiation and motility of human pancreatic stellate cells and fibroblasts. Conclusions: These data suggest that SHH contributes to the formation of desmoplasia in pancreatic cancer, an important component of the tumor microenvironment.Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, resulting in 30,000 deaths each year, in part because it is one of the most lethal cancers with a death-to-incidence ratio of 0.99 (1). The lethality of pancreatic cancer is largely due to late stage of diagnosis and resistance to current therapies. More than 80% of patients are unresectable and most present with metastatic disease due to aggressive localized invasion and a high incidence of early metastasis (2). Worldwide, the incidence of death from pancreatic cancer has increased, which, together with the lack of current therapies, emphasizes the need to determine the mechanisms of pancreatic cancer progression and better targets for diagnosis and treatment.The current model of pancreatic cancer progression includes mutations that activate K-ras, followed by inactivating mutations or loss of expression of tumor suppressor genes including p53, p16INK4A , and SMAD4 (3). Sonic hedgehog (SHH) and other proteins downstream of the hedgehog pathway were recently detected in precursor lesions and samples of primary tumors from patients with pancreatic adenocarcinoma, which implicates this pathway in the initiation and progression of pancreatic cancer given its absence in normal adult pancreas (4, 5). Transgenic mouse models in which SHH was expressed in mouse pancreatic epithelium, in concert with activated Ras signaling, enhanced the formation of pancreatic intraepithelial neoplasia and accelerated lethality, further supporting a role for hedgehog as an early contributor to this lethal disease (6). We investigated the contribution of SHH to pancreatic cancer progression by expressing SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), which was described previously (7,8). This cell line has been documented to represent an appropriate and important model system to delineate signaling mechanisms for Ras-mediated oncogenesis and growth of pancreatic ductal epithelial cells (8), and...