Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer

Carethers, John M.; Smith, Edward J.; Behling, Cynthia; Nguyen, Lanchinh; Tajima, Akihiro; Doctolero, Ryan T.; Cabrera, Betty L.; Goel, Ajay; Arnold, Christian; Miyai, Katsumi; Boland, C. Richard

doi:10.1053/j.gastro.2003.12.023

Cited by 411 publications

(303 citation statements)

References 21 publications

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“…mutations in a number of metastasis-promoting genes. However, the presence of an antimetastatic immune protection in MSI-H CRC patients may explain recent findings that adjuvant 5-FU chemotherapy has no beneficial or even adverse effects in this collective (Ribic et al, 2003;Carethers et al, 2004). Further functional studies are needed to clarify the molecular mechanisms underlying these phenomena.…”

Section: Discussionmentioning

confidence: 97%

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

et al. 2005

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Colorectal carcinomas (CRCs) with high microsatellite instability (MSI-H) share clinicopathological features distinctly different from their microsatellite stable (MSS) counterparts. Unlike MSS cancers, MSI-H CRCs occur predominantly in the right-sided colon and are often characterised by a strong lymphocyte infiltration. A poor differentiation pattern is found in most MSI-H CRCs, even though patients with MSI-H carcinomas seem to have a significantly longer survival after surgical resection. To clarify which factors contribute to the obvious paradoxon of a more favourable prognosis of MSI tumours, several clinical and histopathological features as well as the microsatellite status were evaluated in 120 colorectal cancer cases fulfilling clinical criteria (Bethesda) indicative for familial colorectal cancer. Microsatellite instablity status and lymphocyte infiltration were related to tumour stage and patients' follow-up. Statistical analysis confirmed well-known relations, such as enhanced lymphocyte infiltration accompanied by Crohn's like reaction (CLR) in MSI-H cancers (CLR þ in 27 out of 47 MSI-H vs 14 out of 71 MSS CRCs, Po0.001). However, after stratification for depth of local invasion and penetration of the primary tumour, T3 tumours displaying MSI had a significantly lower rate of distant metastases (M1 in four out of 35 MSI-H vs 20 out of 41 MSS CRCs, Po0.001). A similar tendency was observed for CLR-positive CRCs (M1 in six out of 29 CLR þ vs 17 out of 45 CLRÀ CRCs, P ¼ 0.13). In a logistic regression model, the MSI-H phenotype and the presence of CLR were independent predictors of a low UICC stage (P ¼ 0.006 and 0.04, respectively). These data, together with the recent definition of highly immunogenic neo-antigens expressed in MSI-H tumour cells, suggest that MSI-H CRCs elicit a protective host response that may prevent metastasis formation.

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Section: Discussionmentioning

confidence: 97%

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

et al. 2005

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“…In the U.S., two small studies reported microsatellite instability in 16.9% 36 and 19.0% 37 of Latinos. In Puerto Rico, a larger retrospective study investigated an unselected group of Latino patients with CRC, on whom IHC staining of only two MMR proteins (MLH1 and MSH2) was performed 22 .…”

Section: Discussionmentioning

confidence: 99%

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Ricker

Hanna

Peng

et al. 2017

Cancer

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Background The landscape of hereditary syndromes and clinicopathologic characteristics among U.S. Latinos/Hispanics with colorectal cancer (CRC) remains poorly understood. Methods A total of 265 CRC patients enrolled in the Hispanic Colorectal Cancer Study were included in this study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data was abstracted from clinical charts. Tumor studies and germline genetic testing results were collected from medical records or performed using standard molecular methods. Results The mean age at diagnosis was 53.7 years (SD=10.3), and 48.3% were female. Overall, 21.2% reported a first- or second-degree relative with CRC; 3.4% met Amsterdam I/II criteria. With respect to Bethesda guidelines, 38.5% met at least one criterion. Of the 161 individuals who had immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing performed, 21 (13.0%) had mismatch repair (MMR) deficient tumors. dMMR tumors were associated with female sex (61.9%), earlier age of diagnosis (50.4 ± 12.4 years), proximal location (61.9%), and first (23.8%) or second (9.5%) degree family history of CRC. Among individuals with dMMR tumors, 13 (61.9%) had a germline MMR mutation (MLH1=6, MSH2=4, MHS6=2, and PMS2=1). We identified two additional MLH1 mutation carriers by genetic testing who had not received IHC/MSI testing. In total, 5.7% of the entire cohort were confirmed cases of Lynch syndrome. Additionally, six individuals (2.3%) had a polyposis phenotype. Conclusions The proportion of dMMR tumors in Latinos (13%) is similar to estimates in non-Hispanic Whites. The majority of individuals with dMMR tumors were confirmed to have Lynch syndrome.

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“…In a review article presenting the MSI frequency from selected papers, true MSI (MSI-H) CRC ranged from 3 to 23% (Tomlinson et al, 2002), whereas previously it had been estimated that out of 50 papers on CRCs, more than 50% overestimated the prevalence of MSI by more than two times (Perucho et al, 1999). This confusion has practical implications in classifying MSI CRCs with respect to their clinico-pathological features, natural history and response to chemotherapy (Watanabe et al, 2001;Ribic et al, 2003;Carethers et al, 2004); yet, nowadays it is not infrequent to encounter prevalence of the MSI CRCs close to or above 20%, which is likely an off-the-mark picture (Boland, 2007;Kim et al, 2007). It should be emphasized that immunohistochemical analysis performed alongside MS-status determination can also help to elucidate whether a CRC is really MMR-deficient and, thereby, a true MSI CRC rather than an MSS one (Thibodeau et al, 1996Dietmaier et al, 1997).…”

Section: The Operative Definition Of Msimentioning

confidence: 99%

Differences and evolution of the methods for the assessment of microsatellite instability

2008

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Microsatellite instability (MSI) originates from the systematic accumulation of uncorrected deletion/insertion in repetitive DNA tracts in cancer cells with a deficient mismatch repair system. Among colorectal cancers, the MSI signature identifies hereditary cases arising in patients with germline mutations in hMLH1, hMSH2, PMS2 and a fraction of those with hMSH6 mutations, as well as sporadic cancers with epigenetic hMLH1 promoter hypermethylation. Considering the specific pathogenesis, pathological features, natural history and response to 5-fluoro-uracil-based chemotherapy of the MSI cancers, confusion about the genetic markers for MSI recognition seems surprising. In this clinically relevant field, an agreement has not been reached concerning the use of di-or mononucleotide markers for MSI assessment. The Revised Bethesda Guidelines still recommend a panel of markers consisting of mono-and dinucleotides, despite being questioned whether it is congruous to continue to use dinucleotide markers for MSI identification. In any event, no single marker is accurate enough for MSI testing, and an awareness of their pros and cons is required for proper interpretation of results. In recent years, several papers have reported different prevalence of MSI in unrelated series, largely depending on the detection and classification method, suggesting that MSI test interpretation also requires the understanding of the phenomenon rather than simply the crude satisfaction of panel recommendations. Inaccuracies can otherwise lead to under-or overdiagnosis and inaccurate disease classification, which always have a negative impact on the clinical practice of medicine.

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Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer

Cited by 411 publications

References 21 publications

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Differences and evolution of the methods for the assessment of microsatellite instability

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