Clinical Management of Lynch Syndrome: Revised Guidelines
Clinical Management of Lynch Syndrome: Revised Guidelines
LS was first described by Aldred Warthin in 1913. In 1966, Henry Lynch reported two large families with hereditary CRC from the midwest. Since then, many hundreds of families with the same pattern of cancer occurrence have been identified throughout the world. In the early 1990s the underlying gene defect was discovered, that is, a mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2. Recently, two groups reported that a constitutional 3' end deletion of EPCAM, which is immediately upstream of the MSH2 gene, may cause LS through epigenetic silencing of MSH2.
An MMR gene defect leads through loss of the corresponding normal alleles in the tumours of carriers to loss of MMR function and results in an accumulation of mutations in (coding and non-coding) microsatellites in such tumours (so-called microsatellites instability; MSI). Carriers of an MMR gene mutation have a very high risk of developing CRC (25–70%) and EC (30–70%) and an increased risk of developing other tumours. The main clinical features are an early age of onset and the occurrence of multiple tumours.
Since 2007, many studies have been published on the risk of developing non-CRC, non-EC cancers in carriers of an MLH1 gene mutation, MSH2 gene mutation and MSH6 gene mutation. Such studies are not yet available for carriers of a PMS2 gene mutation. A summary of the findings is shown in Table 2. Those new studies also reported increased risks for pancreatic, bladder and breast cancer and possibly prostate cancer. Notably, carriers of MSH6 mutations appear to be particularly at risk of gastrointestinal cancer and EC, whereas carriers of an MSH2 gene mutation have the highest cancer risks across the spectrum, especially for the development of urinary tract cancer. The risks for MLH1 gene mutation carriers are between the cancer risks reported for MSH6 carriers and those for MSH2 carriers.
Moreover, a recent study reported on increased cancer risks for individuals with an EPCAM deletion. The investigators compared the cancer risks between 194 carriers of an EPCAM deletion and 473 carriers of a mutation in MLH1, MSH2, MSH6 or a combined EPCAM–MSH2 deletion. The risk of developing CRC for EPCAM deletion carriers was similar (75% by age 70 years) to the risks in carriers of an MLH1 or MSH2 mutation or a combined EPCAM–MSH2 deletion but was higher than the risk in MSH6 mutation carriers. By contrast, the risk of EC (12% by age 70 years) was significantly lower in female carriers of an EPCAM deletion compared to the risk in carriers of an MSH2 or MSH6 mutation or a combined EPCAM–MSH2 deletion. The EC risk in EPCAM deletion carriers was also lower than the risk in MLH1 carriers but this difference was not statistically significant.
The wide variation in cancer risk within and between families is direct evidence that the risk is influenced by environmental and genetic factors. In the past 5 years many genome-wide association studies in CRC patients have identified a total of 20 variants that are associated with an increased risk of sporadic CRC. A Dutch study evaluated whether six of these variants act as modifiers of the CRC risk in 675 gene mutation carriers. Two variants (rs16892766 and rs3802842) were reported to increase the CRC risk in LS, the latter only in female carriers. An Australian group evaluated the effect of nine variants on the CRC risk in 684 MMR gene mutation carriers. They confirmed the association of the previously reported variants with CRC risk but only for MLH1 carriers. A French group did not find an association between these and other variants in 748 mutation carriers. In summary, more studies are needed to define the role of these variants in clinical practice.
Short Update on LS
LS was first described by Aldred Warthin in 1913. In 1966, Henry Lynch reported two large families with hereditary CRC from the midwest. Since then, many hundreds of families with the same pattern of cancer occurrence have been identified throughout the world. In the early 1990s the underlying gene defect was discovered, that is, a mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2. Recently, two groups reported that a constitutional 3' end deletion of EPCAM, which is immediately upstream of the MSH2 gene, may cause LS through epigenetic silencing of MSH2.
An MMR gene defect leads through loss of the corresponding normal alleles in the tumours of carriers to loss of MMR function and results in an accumulation of mutations in (coding and non-coding) microsatellites in such tumours (so-called microsatellites instability; MSI). Carriers of an MMR gene mutation have a very high risk of developing CRC (25–70%) and EC (30–70%) and an increased risk of developing other tumours. The main clinical features are an early age of onset and the occurrence of multiple tumours.
Since 2007, many studies have been published on the risk of developing non-CRC, non-EC cancers in carriers of an MLH1 gene mutation, MSH2 gene mutation and MSH6 gene mutation. Such studies are not yet available for carriers of a PMS2 gene mutation. A summary of the findings is shown in Table 2. Those new studies also reported increased risks for pancreatic, bladder and breast cancer and possibly prostate cancer. Notably, carriers of MSH6 mutations appear to be particularly at risk of gastrointestinal cancer and EC, whereas carriers of an MSH2 gene mutation have the highest cancer risks across the spectrum, especially for the development of urinary tract cancer. The risks for MLH1 gene mutation carriers are between the cancer risks reported for MSH6 carriers and those for MSH2 carriers.
Moreover, a recent study reported on increased cancer risks for individuals with an EPCAM deletion. The investigators compared the cancer risks between 194 carriers of an EPCAM deletion and 473 carriers of a mutation in MLH1, MSH2, MSH6 or a combined EPCAM–MSH2 deletion. The risk of developing CRC for EPCAM deletion carriers was similar (75% by age 70 years) to the risks in carriers of an MLH1 or MSH2 mutation or a combined EPCAM–MSH2 deletion but was higher than the risk in MSH6 mutation carriers. By contrast, the risk of EC (12% by age 70 years) was significantly lower in female carriers of an EPCAM deletion compared to the risk in carriers of an MSH2 or MSH6 mutation or a combined EPCAM–MSH2 deletion. The EC risk in EPCAM deletion carriers was also lower than the risk in MLH1 carriers but this difference was not statistically significant.
The wide variation in cancer risk within and between families is direct evidence that the risk is influenced by environmental and genetic factors. In the past 5 years many genome-wide association studies in CRC patients have identified a total of 20 variants that are associated with an increased risk of sporadic CRC. A Dutch study evaluated whether six of these variants act as modifiers of the CRC risk in 675 gene mutation carriers. Two variants (rs16892766 and rs3802842) were reported to increase the CRC risk in LS, the latter only in female carriers. An Australian group evaluated the effect of nine variants on the CRC risk in 684 MMR gene mutation carriers. They confirmed the association of the previously reported variants with CRC risk but only for MLH1 carriers. A French group did not find an association between these and other variants in 748 mutation carriers. In summary, more studies are needed to define the role of these variants in clinical practice.
Source...