Cancer risks for MLH1 and MSH2 mutation carriers

Reference details

Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M, Antill YC, Thibodeau SN, Casey G, Gallinger S, Marchand LL, Newcomb PA, Haile RW, Young GP, James PA, Giles GG, Gunawardena SR, Leggett BA, Gattas M, Boussioutas A, Ahnen DJ, Baron JA, Parry S, Goldblatt J, Young JP, Hopper JL, Jenkins MA (2013) Cancer risks for MLH1 and MSH2 mutation carriers. Human mutation 34:490-497


We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001),="" with="" cumulative="" risks="" at="" the="" age="" of="" 70="" years="" estimated="" to="" follow="" u-shaped="" distributions.="" for="" example,="" 17%="" of="" male="" msh2="" mutation="" carriers="" have="" estimated="" lifetime="" risks="" of="" 0%-10%="" and="" 18%="" have="" risks="" of="" 90%-100%.="" therefore,="" average="" risks="" are="" similar="" for="" the="" two="" genes="" but="" there="" is="" so="" much="" individual="" variation="" about="" the="" average="" that="" large="" proportions="" of="" carriers="" have="" either="" very="" low="" or="" very="" high="" lifetime="" cancer="" risks.="" our="" estimates="" of="" crc="" and="" ec="" cumulative="" risks="" for="" mlh1="" and="" msh2="" mutation="" carriers="" are="" the="" most="" precise="" currently="">

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