Splice site mutations in mismatch repair genes and risk of cancer in the general population
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Splice site mutations in mismatch repair genes and risk of cancer in the general population. / Thomsen, Mette; Nordestgaard, Børge G; Tybjærg-Hansen, Anne; Bojesen, Stig E.
In: Familial Cancer, 18.01.2013.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Splice site mutations in mismatch repair genes and risk of cancer in the general population
AU - Thomsen, Mette
AU - Nordestgaard, Børge G
AU - Tybjærg-Hansen, Anne
AU - Bojesen, Stig E
PY - 2013/1/18
Y1 - 2013/1/18
N2 - We tested the hypothesis that splice site variations in MSH2 and MLH1 are associated with increased risk of hereditary non-polyposis colorectal cancer (HNPCC) and of cancer in general in the general population. In a cohort of 154 HNPCC patients with sequenced MSH2 and MLH1, we identified four possible splice-site mutations, which we subsequently genotyped in more than 9,000 individuals from the general population. Allele frequencies in the general population were 0 % for 942+3A>T in MSH2, 0.05 % for 307-19A>G, 0.005 % for 1,667+(2-8)del(taaatca);ins(attt), and 4.4 % for 1039-8T>A in MLH1. Odds ratios for HNPCC in a case-control design were 419 (95 % CI: 53-18,900) for 942+3A>T in MSH2, 19 (5-72) for 307-19A>G, 194 (21-1,768) for 1,667+(2-8)del(taaatca); ins(attt), and 0.3 (0.1-0.7) for 1,039-8T>A in MLH1. In the general population, incidence rate ratios for 1,039-8T>A carriers versus noncarriers were 0.70 (0.51-0.96) for HNPCC-related cancers combined and 0.82 (0.71-0.94) for all cancers combined in a prospective design. The three rare mutations were associated with increased risk of HNPCC. In contrast, the more common 1,039-8T>A associated with a decreased risk of HNPCC, of HNPCC-related cancers and of all cancers combined in the general population. These findings are novel and important in the counseling of HNPCC patients and their relatives.
AB - We tested the hypothesis that splice site variations in MSH2 and MLH1 are associated with increased risk of hereditary non-polyposis colorectal cancer (HNPCC) and of cancer in general in the general population. In a cohort of 154 HNPCC patients with sequenced MSH2 and MLH1, we identified four possible splice-site mutations, which we subsequently genotyped in more than 9,000 individuals from the general population. Allele frequencies in the general population were 0 % for 942+3A>T in MSH2, 0.05 % for 307-19A>G, 0.005 % for 1,667+(2-8)del(taaatca);ins(attt), and 4.4 % for 1039-8T>A in MLH1. Odds ratios for HNPCC in a case-control design were 419 (95 % CI: 53-18,900) for 942+3A>T in MSH2, 19 (5-72) for 307-19A>G, 194 (21-1,768) for 1,667+(2-8)del(taaatca); ins(attt), and 0.3 (0.1-0.7) for 1,039-8T>A in MLH1. In the general population, incidence rate ratios for 1,039-8T>A carriers versus noncarriers were 0.70 (0.51-0.96) for HNPCC-related cancers combined and 0.82 (0.71-0.94) for all cancers combined in a prospective design. The three rare mutations were associated with increased risk of HNPCC. In contrast, the more common 1,039-8T>A associated with a decreased risk of HNPCC, of HNPCC-related cancers and of all cancers combined in the general population. These findings are novel and important in the counseling of HNPCC patients and their relatives.
U2 - 10.1007/s10689-013-9601-7
DO - 10.1007/s10689-013-9601-7
M3 - Journal article
C2 - 23329266
JO - Familial Cancer
JF - Familial Cancer
SN - 1389-9600
ER -
ID: 48538524