Association of MUTYH and MSH6 germline mutations in colorectal cancer patients.
Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3'UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.
Giráldez
María Dolores
MD
Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Catalonia, Barcelona, Spain.
Balaguer
Francesc
F
Caldés
Trinidad
T
Sanchez-de-Abajo
Ana
A
Gómez-Fernández
Nuria
N
Ruiz-Ponte
Clara
C
Muñoz
Jenifer
J
Garre
Pilar
P
Gonzalo
Victoria
V
Moreira
Leticia
L
Ocaña
Teresa
T
Clofent
Joan
J
Carracedo
Angel
A
Andreu
Montserrat
M
Jover
Rodrigo
R
Llor
Xavier
X
Castells
Antoni
A
Castellví-Bel
Sergi
S
D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016133:Polymerase Chain Reaction
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
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