In this study in which all national activity was compiled, we found that most families with MLH1 mutations were identified by any of the clinical criteria used. The criteria that included extracolonic cancers (AMSII) identified two out of three MSH2 mutations, whereas MSH6 mutations were not identified with reasonable sensitivity by any of the single clinical criteria. As these results were obtained after expanding all mutation-carrying kindreds, we consider them to be maximum estimates. The sensitivities for detecting mutation-positive families upon referral were lower.
The most sensitive single clinical criterion for identifying MSH6 mutation carriers was the presence of two independent primary cancers (BII_2) (). This information is, however, awaiting detailed validation of diagnoses in the families and may not be easily obtainable when interviewing a family member.
We have recently reported that, when applied to a consecutive series of unselected patients with CRC, the sensitivities of AMSII and BII criteria were as low as 25% and 50%, respectively.12
Moreover, awareness of hereditary cancer among clinicians involved in diagnosis and treatment of CRC is low, and families actually meeting the criteria may not be identified.24
These points highlight the challenges associated with using family history for detecting families with MMR mutations. Our combined findings support the suggestion by the Mallorca group to apply IHC and/or MSI analysis to all CRCs to identify MMR mutation carriers.25
mutation carriers are likely to develop extracolonic cancers, it may be justified to suggest that all cancer phenotypes associated with Lynch syndrome should be subjected to IHC and/or MSI analysis and subsequent DNA mutation analysis. Until such studies have been performed, we remain cautious when discussing the prevalence of MSH6
mutations. Correspondingly, the current estimates of penetrance/expression of MSH6
mutations may be (partly) derived from families fulfilling current clinical criteria.26 27
These estimates may be misleading, as they may reflect the criteria used to select the families from which the estimates were derived.
mutations were less common than assumed from previous reports,8
mutations accounted for almost half of all kindreds with a mutation. Despite the fact that the criteria used were insensitive for detecting MSH6
mutations, the number of MSH6
mutation-carrying kindreds were higher than MLH1
None of the mutations were common enough to affect the distribution significantly, with respect to neither number of mutation-carrying kindreds nor number of mutation-carrying people. Despite the difference in prevalence of mutations in the different genes, the mean number of mutation carriers per family was similar for all the genes.
A Danish study reported a relatively high prevalence of MSH6
If this were due to similarities between these neighbouring populations, we would have expected to detect founder mutation(s) in both populations, but this was not the case. The reason for the similar results may be the study designs. Both studies applied wide criteria for IHC and MSI analysis.
The number of carriers of PMS2
mutations was insufficient for sophisticated statistical analysis. Part of the explanation may be that testing for PMS2
mutations has not been available for as long as testing for mutations in the other genes. Also, most of the few PMS2
mutation carriers were included in several branches of one old family. Some of these branches were not identified by IHC, but the tumours displayed MSI (MSI-high). Thus, by performing only IHC and not MSI analysis to prescreen for mutation testing, a few mutations may have been missed. This indicates that MSI analysis is of importance if IHC shows normal expression of all MMR genes. MMR mutations cannot be excluded if neither analysis has been performed. Technical problems involved in DNA PMS2
mutation analyses are well known.28–30
Current procedures (including both technical aspects and clinical criteria) may be insufficient to detect PMS2
mutations, and current estimates of prevalence of PMS2
mutations may be too low.
IHC was used as a selection criterion for mutation analysis and could not be scored as a result. The result of all efforts to examine selected families without abnormal IHC or MSI for mutations was the identification of a single mutation-carrying family (family S254, MSH6
c.1405delT). The study was not designed to assess sensitivity of IHC/MSI, and we will not discuss this further. Our impression from other reports is, however, that IHC and MSI analyses are more sensitive than any clinical criteria for identifying kindreds carrying MSH2
mutations, in particular,11 12
and the present report is in keeping with that notion.
In conclusion, we observed that 87% of families with an MLH1
mutation, 62% with an MSH2
mutation, but less than half of families with an MSH6
mutation were identified by the AMSII criteria. Each of the clinical Bethesda criteria when considered individually also showed low sensitivity. We have, however, previously demonstrated that these criteria were neither sensitive nor specific in an unselected series of CRC cases. Our combined observations indicate that the prevalence of MSH6
mutations may be higher than currently assumed, and their penetrance and expression may differ from what is currently assumed. These findings are in keeping with the Mallorca guidelines, which recommend that MSI analysis and/or IHC should be performed on all CRCs.25
In addition, we suggest that such testing should be applied to all incident cancers in the Lynch syndrome tumour spectrum to increase the rate of detection of MMR mutation carriers.