NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019

Abstract

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue

“…Patients with a dysfunctional mismatch repair (MMR) system are at high risk for developing CRC [8]. Thus, a timely and accurate diagnosis is important in order to implement an appropriate program of surveillance, which improves long-term survival in individuals carrying a MMR gene defect.…”

“…Patients with LS have markedly increased lifetime risk of CRC and endometrial cancer (EC), as well as ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, small intestine, pancreatic and sebaceous skin cancers [3][4][5][6][7]. The penetrance of LS is approximately 52% for CRC, 57% for EC, 38% for ovarian, and less than 20% for other previously mentioned cancers [8]. Early detection of LS is therefore of great importance, since prophylactic surgery may effectively prevent endometrial and ovarian cancer [9,10] while colonoscopy surveillance has been proven to reduce morbidity and mortality in CRC by 65% to 70% [11][12][13].…”

Cancer Genetics and Therapeutic Opportunities in Urologic Practice

“…If tumor tissue is available, immunohistochemistry and MSI-PCR should be performed to evaluate for the lack of MMR proteins and amount of MSI, respectively. Should these tests demonstrate a patient is at high risk for Lynch syndrome, through either a lack of proper MMR proteins (i.e., MLH1, MSH2, MSH6, or PMS2) or MSI-high, they should undergo germline genetic testing to confirm the diagnosis of Lynch syndrome [103]. Lastly, there is no clear consensus regarding how patients with Lynch Syndrome should be screened for urinary tract carcinoma.…”

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

“…In the oligopoliposis group, we detected deleterious mutations in 8/25 (32.0%) patients. In six of these patients, the variants were present in known highly penetrant genes associated with either autosomal dominant (two in APC and one in BMPR1A) or recessive (two in MUTYH and one in NTHL1) polyposis syndromes, and two in genes with moderate penetrance (one in CHEK2 and BLM each) [21,22]. In addition, 5/25 (20.0%) patients were carriers of monoallelic deleterious variants in known genes associated with MUTYH associated polyposis (MAP), and NTHL1 associated polyposis (NAP), autosomal recessive polyposis syndromes (three in MUTYH and two in NTHL1, respectively).…”

“…The twist transcription factor, encoded by the TWIST1 gene (TWIST1; OMIM* 601622) is a member of the basic helix loop helix transcription factor family and has an ORIGINAL ARTICLE HEREDITARY CRC IN MACEDONIANS pathogenic variants [22,23]. In 12/25 (48%) patients we did not detect any pathogenic variant, further supporting the notion that the molecular basis of this condition is highly heterogenous and probably involves defect(s) in other gene(s) not tested in our assay [24].…”