The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3,4,5,6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

BACKGROUND & AIMS The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, non-invasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRI). METHODS We screened 225 asymptomatic adult HRI at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. RESULTS Ninety-two of 216 HRI (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n=5) by any of the imaging modalities. Fifty-one of the 84 HRI with a cyst (60.7%) had multiple lesions, typically small (mean 0.55 cm, range 2–39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects <50 years old, 34% of subjects 50–59 years old, and 53% of subjects 60–69 years old (P<.0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRI, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRI (82 intraductal papillary mucinous neoplasms [IPMN] and 3 pancreatic endocrine tumors). Three of 5 HRI who underwent pancreatic resection had high-grade dysplasia in <3 cm IPMNs and in multiple intraepithelial neoplasias. CONCLUSIONS Screening of asymptomatic HRI frequently detects small pancreatic cysts, including curable, non-invasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT.

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In the United States, colorectal cancer (CRC) is the third most common and second most lethal cancer. More than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) have a young onset (ie, occurring in individuals younger than 50 years). The CRC incidence and mortality rates are decreasing among all age groups older than 50 years, yet increasing in younger individuals for whom screening use is limited and key symptoms may go unrecognized. Familial syndromes account for approximately 20% of young-onset CRCs, and the remainder are typically microsatellite stable cancers, which are more commonly diploid than similar tumors in older individuals. Young-onset CRCs are more likely to occur in the distal colon or rectum, be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Yet, stage-specific survival in patients with young-onset CRC is comparable to that of patients with later-onset cancer. Primary care physicians have an important opportunity to identify high-risk young individuals for screening and to promptly evaluate CRC symptoms. Risk modification, targeted screening, and prophylactic surgery may benefit individuals with a predisposing hereditary syndrome or condition (eg, inflammatory bowel disease) or a family history of CRC or advanced adenomatous polyps. When apparently average-risk young adults present with CRC-like symptoms (eg, unexplained persistent rectal bleeding, anemia, and abdominal pain), endoscopic work-ups can expedite diagnosis. Early screening in high-risk individuals and thorough diagnostic work-ups in symptomatic young adults may improve young-onset CRC trends.

Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genome of 638 familial pancreatic cancer patients. We also sequenced the exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types.

Genome-wide sequencing identified heterozygous, constitutional, Ataxia telangiectaisa mutated (ATM) gene mutations in two kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wildtype allele. Sequence analysis of an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene, while no deleterious mutations were identified in 190 spouse controls (p=0.046). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition.

All cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair, 1,2 but not all of these mutations are inherited from a parent. For example, sporadic mutations can occur in somatic/ tumor cells only, and de novo mutations can occur for the first time in a germ cell (i.e., egg or sperm) or in the fertilized egg itself during early embryogen-The NCCN