Recent Discoveries in the Genetics of Familial Colorectal Cancer and Polyposis

Yurgelun

CA A Cancer J Clinicians

2018

129

106

The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

Section: Germline Basis Of Familial Crcmentioning

confidence: 99%

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

Yurgelun

CA A Cancer J Clinicians

2018

129

106

“…Lynch syndrome (LS), the single most common inherited cause of CRC, shows an autosomal dominant pattern of inheritance due to germline mutations in either of the genes MLH1 , MSH2 , MSH6 , PMS2 , or EPCAM which eventually results in the disruption of DNA mismatch repair (MMR) in LS tumor cells (for reviews, see Kohlmann and Gruber 2004, Lynch et al 2015). There are several other less common hereditary conditions that confer increased risk for CRC, mainly familial adenomatous polyposis (FAP or APC -associated polyposis caused by mutations in the APC gene), MUTYH -associated polyposis (MAP; mutations in MUTYH ), juvenile polyposis syndrome (JPS; BMPR1A , SMAD4 ), PTEN hamartoma tumor syndrome (PHTS; PTEN ), Peutz-Jeghers syndrome (PJS; STK11 ), and polymerase proofreading-associated polyposis (PPAP; POLE and POLD1 ) (for review, see Valle 2017). …”

Section: Introductionmentioning

confidence: 99%

Hereditary colorectal cancer diagnostics in southern Sweden: retrospective evaluation and future considerations with emphasis on Lynch syndrome

Henriksson¹,

Henriksson²,

Ehrencrona

et al. 2018

J Community Genet

Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed.Electronic supplementary materialThe online version of this article (10.1007/s12687-018-0385-1) contains supplementary material, which is available to authorized users.

“…Autosomal recessive forms of polyposis are caused by biallelic inactivation of the base excision repair genes MUTYH and NTHL1 and of the DNA mismatch repair genes MSH3 , PMS2 , MSH6 , MSH2 , MLH1 , and MLH3 . Other genes, such as GREM1 and RNF43 have been associated with mixed and serrated polyposis respectively, and different forms of hamartomatous polyposes are caused by germline mutations in SMAD4 and BMPR1A (Juvenile polyposis), STK11 (Peutz Jeghers), or PTEN (PTEN‐hamartoma‐tumor syndromes) (reviewed by Olkinuora et al, ; Valle, ).…”

Section: Introductionmentioning

confidence: 99%

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

et al. 2019

Self Cite

Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5–2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.