Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma
Introduction
Knowledge about colorectal cancers with microsatellite instability (MSI) has grown significantly since the initial discovery of MSI in colorectal cancer in 1993.1, 2, 3 The genetic basis for MSI has been found to be a defective DNA mismatch repair (MMR) system and two major mechanisms responsible for causing such deficiencies have been uncovered. One is germline mutation in one of the major MMR genes, namely, MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6), and PMS2 (postmeiotic segregation increased 2), or deletions in the EPCAM gene that cause allele-specific MSH2 inactivation. Germline mutation in an MMR gene or EPCAM defines Lynch syndrome (LS). The second major mechanism relates to a somatic occurrence of promoter methylation of MLH1, often in the context of CpG island methylator phenotype (CIMP). This mechanism leads to sporadic MSI colorectal cancers.
MSI colorectal cancers are found to have distinctive clinicopathological features. They arise primarily in the right colon and tend to be locally bulky, but are less likely to have nodal or distant metastasis. While most MSI colorectal cancers are gland forming similar to their non-MSI counterparts, they tend to have conspicuous tumor-infiltrating lymphocytes and often contain a second or third histologic pattern, which results in histologic heterogeneity. Other histological features over-represented in MSI cancers include mucinous and signet-ring–cell components, and the so-called “medullary” pattern. Significantly, the MSI phenotype has been shown to impact on prognosis and treatment response. In general, MSI colorectal cancers have a better prognosis than their non-MSI counterparts, and patients with MSI colorectal cancers may not benefit from 5-fluorouracil therapy.4, 5 Furthermore, ongoing efforts on immunotherapeutic approaches targeting the MSI phenotype and its associated tumor-infiltrating lymphocytes may offer further treatment options for MSI colorectal cancers.6
Perhaps, the most significant development in the field of MSI in recent years is the growing awareness of LS and the widespread efforts on its detection and management.1 There have been data indicating that the cancer incidence and mortality in LS patients and their family members can be significantly reduced by stringent surveillance protocols3 and preventive measures.7 Consequently, there has been a steady increase in the attention and effort devoted to the detection of this syndrome.
Today, as knowledge about LS and MSI cancers translates to better clinical practice, it is particularly worth directing our attention to the most updated definitions of these conditions, and also to the specific utilities of the various testing tools and strategies that are being used to detect these conditions. Incorporation of the most up-to-date knowledge and technology is the key to ensure the most precise diagnosis and consequently the most precise management of these diseases.
Section snippets
A brief historical overview
MSI in colorectal cancer was first discovered in 1993. This discovery was preceded by decades of clinical investigation that dated back to 1913 when a pathologist, Aldred Warthin, first documented the phenomenon of cancer heredity. Significant developments in the decades of clinical investigation following Warthin׳s initial observation include the description of hereditary non-polyposis colorectal cancer (HNPCC) by Henry Lynch, the formation of the international collaborative group on HNPCC
Updated molecular definitions for Lynch syndrome and its related conditions
The knowledge gained since the discovery of MSI in colorectal carcinoma has allowed a new molecular approach to the classification of MMR deficiency-associated familial and sporadic colorectal cancers. Over the last two decades, as new data continually emerged and concepts evolved, the naming of the syndrome and its related conditions changed. Fig. 1 summarizes this dynamic process. The current definitions for the various conditions are described below.
Lynch syndrome (LS) (MIM no. 120435-6) is
The tools and strategies for detecting Lynch syndrome and related conditions
The task of detecting LS probands among colorectal cancer patients is at the current time carried out via a screening strategy. Various tools that bear informative value in predicting MMR deficiency are being pursued in an algorithmic fashion.
The evolving nature of mismatch repair testing in colorectal carcinoma
The field of MSI and LS detection is one that has been continuously evolving as technology has advanced and new knowledge has emerged. The current universal approach is being achieved after we have gone through phases of relying solely on family history (the era of Amsterdam criteria) to incorporate MSI testing into family history and other clinical data (the era of Bethesda guidelines). As we are now immersed in an era of massively parallel sequencing and individualized medicine, the detection
Acknowledgment
This work is supported by NIH R01 grant CA164944-01A1.
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