*LS-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[228,229]
Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations in MSH6.[230,231,232,233,234] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.
Genetic/Molecular testing for LS
Genetic risk assessment of LS generally considers the cancer family history and age at diagnosis of CRC and/or other LS-associated cancers in the patient. Studies of gene testing using DNA sequencing in suspected LS probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative MSH2 or MLH1 mutation, allowing genetically informed management strategies to be developed for the family.[235,236] Computer models analogous to BRCAPro predict the probability of a MMR gene mutation. PREMM1, PREMM2, PREMM6, and the MMRPro models are easy to use and have been validated.[237,238,239] Although these models can predict mutation even in the absence of MSI or IHC information, they can incorporate those data as available. All three computer prediction models take family history of endometrial cancer into account. The mutation detection rate is higher for patients with more striking family histories or with informative tumor testing.
In the absence of additional family or personal history suggestive of LS, isolated cases of CRC diagnosed prior to age 36 years are uncommonly associated with MMR gene mutations. One study found MMR mutations in only 6.5% of such individuals. Therefore, isolated cases of very early onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline mutation analysis.
MSI/IHC in adenomas
Current practice is to offer colonoscopy surveillance to those with strong family histories but no prior genetic or tumor testing. At times, adenomas are detected during these colonoscopies. In the instance when an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR mutations found 8 of 12 adenomas to have both MSI and IHC protein loss. However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude LS.
Microsatellites are short, repetitive sequences of DNA (often mononucleotides, dinucleotides, or trinucleotides) located throughout the genome, primarily in intronic sequences.[242,243] The term microsatellite instability (MSI) is used when tumor DNA shows alterations in microsatellite regions when compared to normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic or germline mutations or epigenetic alterations. In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all MSI-H tumors.