Updates in the field of hereditary nonpolyposis colorectal cancer : Expert Review of Gastroenterology & Hepatology

ABSTRACT Introduction Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment. Areas covered The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed. Expert commentary LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.Peer reviewe

Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1(+/-)) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.Peer reviewe

Insights in germline genetic variation in Hereditary Polyposis Syndromes Patients from Argentina and Chile: identification of 4 novel variants

We aimed to identify novel genetic variants in 81 unrelated probands from Argentina and Chile with hereditary polyposis syndromes (Familial Adenomatous Polyposis, FAP, and Hamartomatous). By whole exome sequencing and MLPA, we identified pathogenic variants in 19.8% (16/81) of individuals and included APC (75%, 12/16), MUTYH (18.8%, 3/16) and SMAD4 (6.2%, 1/16) genes. As expected, more than 50% (17/33) of the variants were VUS, being 15 identified in APC, 1 in SMAD4 and 1 in POLE genes. We identified 4 novel potentially pathogenic germline variants in 4.9% (4/81) patients, including APC c.1271dupA (p.E425Gfs*4), c.532T>A (p.F178I), c.4948A>T (p.N1650Y), and SMAD4 c.742C>T (p.Q248*). By analyzing MUTYH gene, we found 2/3 probands carrying compound heterozygous pathogenic SNVs: c.289C>T (p.R97*)/c.1227_1228dupGG (p.E410Gfs*), c.536A>G (p.Y179C)/c.1187G>A (p.G396D). The third case showed a homozygous pathogenic SNV, c.1187G>A (p.G396D). We described a correlation between the identified pathogenic germline variant and the clinical phenotype where 80% of carriers of APC pathogenic variants, having ≥100 colonic adenomatous polyps, developed colorectal cancer (CRC, at mean age=33.5y) and/or has polyposis and CRC family history. Our study enlarges the spectrum of causal variants in other genes than APC and the genotype/phenotype correlation in Argentinean and Chilean patients. Our results may have a direct impact on providing an appropriate genetic counseling and clinical management for individuals and their relatives who carry these variants. The high percentage of identified VUS support the notion that more studies addressing the biological consequence are strongly required, for so improve the translation of genetic research findings into patient care.Fil: Mayordomo, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Cerliani, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Olkinuora, Alisa. University of Helsinki; FinlandiaFil: Piñero, Tamara Alejandra. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Cajal, Andrea Romina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Coraglio, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: Alvarez, Karin. Clinica Las Condes; ChileFil: Cisterna, Daniel. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: Collia Ávila, Karina. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: Gutierrez, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: López Köstner, Francisco. Clinica Las Condes; ChileFil: Dominguez Valentin, Mev. University of Oslo; NoruegaFil: Peltomäki, Paivi. No especifíca;Fil: Vaccaro, Carlos Alberto. Hospital Italiano; ArgentinaFil: Pavicic, Walter Hernan. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; Argentina4th meeting of the European Hereditary Tumour GroupBarcelonaEspañaEuropean Hereditary Tumour Grou