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Hereditary Nonpolyposis Colorectal Cancer (HNPCC or “Lynch syndrome”), involving pathogenic variants in the Mismatch Repair (MMR) genes, is the most common inherited condition that predisposed to colorectal adenomas and colorectal cancer. In this chapter I review the history of HNPCC, from early case reports, to more systematic clinical information and clinical criteria, and finally to the discovery of the MMR genes themselves in 1993, including the key feature of microsatellite instability. This central role for microsatellite analysis of colorectal cancers involves a growing trend toward “universal testing” for evidence of MSI, whether by PCR methods or by immunohistochemistry (IHC). Even though such universal testing has not been completely adopted around the world, we are already evolving toward more routine use of multi-gene “panels” for germline MMR mutation detection. Under these circumstances, one may reasonably ask whether understanding the historical unfolding of clinical features of HNPCC is even relevant. As this chapter hopes to demonstrate, an appreciation of the landscape of HNPCC would not be complete without such a historical perspective, including the important role of Dr Henry Lynch over a lifetime of work in the field.

Cáncer colorrectal No Poliposo Hereditario (HNPCC or “Síndrome de Lynch”), implica variantes patogénicas en los genes de reparación del mal pareamiento de bases del ADN (MMR), es la condición hereditaria más frecuente que predispone a adenomas colorrectales y cáncer colorrectal. En esta revisión se describe la historia de HNPCC, desde los primeros casos clínicos, la información clínica más sistemática, los criterios clínicos y finalmente, al descubrimiento de los propios genes MMR en 1993, incluidas las características claves de la inestabilidad de los microsatélites (MSI). este papel central del análisis de los microsatélites de los cánceres colorrectales implica una tendencia creciente hacia la “prueba universal” para evidenciar la MSI, ya sea por métodos de PCR o por inmunohistoquímica (IHQ). Aunque si bien, la prueba universal no ha sido completamente adoptada alrededor del mundo, nosotros ya estamos evolucionando hacia uso más rutinario de “paneles” de múltiples genes para la detección de mutaciones de línea germinal en genes MMR. Bajo estas circunstancias, uno puede razonablemente preguntarse si la comprensión del desarrollo histórico de las características clínicas de HNPCC es incluso relevante. Como este artículo espera demostrar una apreciación del escenario del HNPCC, ésta no sería completa sin una perspectiva histórica, incluyendo el papel importante del Dr. Henry Lynch sobre toda una vida de trabajo en este campo.

BACKGROUND:Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. METHODS:To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P

ObjectiveLynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity.DesignWe collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions.ResultsOn multivariate analysis, age (≥45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P

Abstract Purpose To compare health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors with sporadic CRC to those with hereditary cancer, specifically Lynch syndrome (LS). Methods Participants completed a mailed self-administered questionnaire that assessed, among other things, demographics, clinical characteristics, and health-related quality of life. Using a case-case design, CRC survivors with LS or sporadic cancer were matched on age, sex, race/ethnicity, cancer stage, geography, and time since diagnosis. Participants were recruited from patient registries at The University of Texas MD Anderson Cancer Center (MD Anderson) (n = 33 LS; n = 75 sporadic) and through social media (n = 42 LS). The final sample included 71 LS and 74 sporadic CRC survivors. Results For LS patients, the mean FACT-C HRQoL score was 84.8 (11.9) [Median = 86.0; Interquartile Range-17] compared to sporadic patients mean score of 85.8 (16.7) [Median = 92.0; Interquartile Range-21], which indicates high quality of life for both groups. LS patients and sporadic CRC patients had similar HRQoL mean scores across 7 different HRQoL metrics, with no significant differences between groups. Exploratory regression analyses indicate some differences in known predictors of HRQoL by group despite no bivariate differences. Conclusions HRQoL is an important component of survivorship in CRC patients. Given the clinical distinctions between LS and sporadic patients, we expected to find significant differences between these patients. However, the patients’ experiences/quality of life does not appear to illustrate such a clear dissimilarity within CRC survivors. Given the limited data in this area, larger studies, ideally with data obtained from multiple sites, is needed to better investigate the alignment between clinical determination and patient experience as well as to explore the relationship between HRQOL, treatment regimens, and health outcomes.