Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation

Abstract

Founder mutations with a large impact in distinct populations have been described in Lynch syndrome. In Denmark, the MLH1 c.1667+2_1667_+8TAAATCAdelinsATTT mutation accounts for 25 % of the MLH1 mutant families. We used the national Danish hereditary nonpolyposis colorectal cancer register to estimate the cumulative lifetime risks for Lynch syndrome-associated cancer in 16 founder mutation families with comparison to 47 other MLH1 mutant families. The founder mutation conferred comparable risks for colorectal cancer (relative risks, RR, of 0.99 for males and 0.79 for females) and lower risks for extracolonic cancer (RR of 0.69 for endometrial cancer and 0.39 for all other extracolonic cancers). We also characterized expression of key Wnt-signaling proteins in colorectal cancers with the founder mutation. Aberrant staining affected β-catenin in 59 %, E-cadherin in 68 %, TCF-4 in 94 % and Cyclin D1 in 68 % with extensive inter-tumor variability despite the same underlying germline mutation. In conclusion, the Danish MLH1 founder mutation that accounts for a significant proportion of Lynch syndrome and is associated with a lower risk for extracolonic cancers.

Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome

“…In 1996, Moisio and colleagues performed genealogical and haplotype analyses in families carrying these two mutations, and not only were the first to describe the existence of founder mutation in LS, but also were able to estimate their age. Around 25% of Danish families that fulfill Amsterdam criteria are carriers of a founder splicing mutation (c.1667+2_1667+8del7ins4) in MLH1 gene (34,35). In Spain, c.306+5G>A and c.1865T>A MLH1 mutations represent the 17.6% of MMR mutations in a specific series of families residing in Catalonia (33).…”

“…In Tenerife Island, the MSH2 c.2063T>G missense variant was considered pathogenic because of the switch of polarity of the aminoacid change (p.Met688Arg) and the conservation between species of the affected residue, which belongs to an important functional domain of the protein (79). In Denmark, the founder mutation c.1667+2_1667+8del7ins4 conferred comparable risks for CRC and lower risks for extracolonic cancer than the other MLH1 mutant Danish families (35). Some founder mutations have been described to cause differential phenotypes.…”

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

“…Many founder mutations associated with LS have been reported in the MLH1 gene [10][11][12][13][14][15]. In Italy, a founder MLH1 mutation was found in six Lynch families originating from a relatively small geographic area of Northern Italy [42,43] and three other have been described in Southern Italy [44].…”

“…inherited by numerous descendants of a common ancestor, have been reported in the MMR genes associated with LS [10][11][12][13][14][15][16][17][18][19][20][21].…”

Muir–Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge

“…Although genotype-phenotype correlations of different MMR gene mutations underline a true genetic heterogeneity in LS, some differences inherent to the phenotype have been highlighted, which can be generalized into a higher susceptibility to colorectal cancer development for MLH1 mutation carriers and into a higher risk of extracolonic tumors and MTS features for those harboring a MSH2 mutation (Lin-Hurtubise et al, 2013). Those general assumptions can be applied also to the founder mutations, with some exceptions: in Denmark, the MLH1 founder mutation has been associated with a lower risk of endometrial and extra-colonic malignancies compared to the general population and other MLH1 mutant families (Therkildsen et al, 2012). The MLH1 founder mutation 2260-2270insT described in the districts of Modena and Reggio Emilia confers a higher tumor burden per individual carrier compared to patients with sporadic MLH1 or MSH2 mutations detected in the same area (Ponz de Leon et al, 2007).…”