MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Abstract

BackgroundApproximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families.MethodsA total of 78 participants (from 29 families) with a mutation in MSH6 and 7 participants (from 6 families) with a mutation in PMS2 were included in the current study. A database of de-identified patient information was analysed to extract all relevant information such as mutation type, cancer incidence, age of diagnosis and cancer type in this Lynch syndrome cohort. Cumulative lifetime risk was calculated utilising Kaplan-Meier survival analysis.ResultsMSH6 and PMS2 mutations represent 10.3% and 1.9%, respectively, of the pathogenic mutations in our Australian Lynch syndrome families. We identified 26 different MSH6 and 4 different PMS2 mutations in the 35 families studied. We report 15 novel MSH6 and 1 novel PMS2 mutations. The estimated cumulative risk of CRC at age 70 years was 61% (similar in males and females) and 65% for endometrial cancer in MSH6 mutation carriers. The risk of developing CRC is different between males and females at age 50 years, which is 34% for males and 21% for females.ConclusionNovel MSH6 and PMS2 mutations are being reported and submitted to the current databases for identified Lynch syndrome mutations. Our data provides additional information to add to the genotype-phenotype spectrum for both MSH6 and PMS2 mutations.

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

“…2001 and Talseth‐Palmer et al. 2010. PMS2 gene analyses were performed at IMVS Pathology, Adelaide, Australia.…”

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

“…In the somatic tumor tissue, mutations in the MMRs genes result in high levels of MSI. [29][30][31][32][33][34] …”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…There is a 44-49% risk of endometrial cancer for female MSH2 mutation carriers (Stoffel et al, 2009). About 10% of Lynch syndrome families have a mutation in MSH6 (Talseth-Palmer et al, 2010). The estimated risk of colorectal cancer in individuals with a MLH6 mutation is lower than some of the other mutations at 30-61% and the risk of endometrial cancer is higher with 65-70% of females developing endometrial cancer by the age of 70 (Talseth-Palmer et al, 2010;Ramsoekh et al, 2009).…”

“…About 10% of Lynch syndrome families have a mutation in MSH6 (Talseth-Palmer et al, 2010). The estimated risk of colorectal cancer in individuals with a MLH6 mutation is lower than some of the other mutations at 30-61% and the risk of endometrial cancer is higher with 65-70% of females developing endometrial cancer by the age of 70 (Talseth-Palmer et al, 2010;Ramsoekh et al, 2009). PMS2 mutations are less frequently the cause of LS accounting for only 2 to 14% of LS cases (Senter et al, 2008;Niessen et al, 2009b;Talseth-Palmer et al, 2010).…”

“…The estimated risk of colorectal cancer in individuals with a MLH6 mutation is lower than some of the other mutations at 30-61% and the risk of endometrial cancer is higher with 65-70% of females developing endometrial cancer by the age of 70 (Talseth-Palmer et al, 2010;Ramsoekh et al, 2009). PMS2 mutations are less frequently the cause of LS accounting for only 2 to 14% of LS cases (Senter et al, 2008;Niessen et al, 2009b;Talseth-Palmer et al, 2010). The cumulative risk by the age of 70 of developing a colon cancer in mono-allelic PMS2 mutation carriers is 15-20%, endometrial cancer is 15% and other Lynch-related cancers is from 25-32% (Senter et al, 2008).…”