The Heterogeneity Between Lynch-Associated and Sporadic MMR Deficiency in Colorectal Cancers

Liu, Guochen; Liu, Ranyi; Yan, Jun; An, Xin; Wu, Jiang; Ling, Yuye; Chen, Jie Wei; Bei, Jin‐Xin; Zuo, Xiao Yu; Cai, Mu Yan; Liu, Zexian; Zuo, Zhi; Liu, Jihong; Pan, Zhizhong; Ding, Pei-Rong

doi:10.1093/jnci/djy004

Cited by 39 publications

(41 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Standardized postoperative monitoring and follow-ups enabled us to detect these metachronous tumors at earlier stages, most of which were cured after complete resection. OS is the most important indicator for evaluating long-term prognosis, and the current study con rms what many studies have already proposed, that LS patients have better long-term prognosis than SCRC patients [7][8][9][10][11][12][13][14][15][16][17].The current study has con rmed that apart from factors intrinsic to the initial primary tumor, such as tumor characteristics, pathological type, and differentiation grade, tumor progression such as recurrence and metastasis is independent prognostic factor affecting long-term survival. Thus, given that microsatellite instability (MSI) tumors experience lower rates of local tumor recurrence, especially at distant sites, than do microsatellite-stable (MSS) tumors [24].CRC displaying MSI that are diagnosed at early stages have a better prognosis compared to CRC displaying MSS [24].…”

Section: Discussionsupporting

confidence: 85%

Comparison of Long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis

Liu

Zheng

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. Comparison of prognosis between LS and sporadic CRC (SCRC) were rare,with conflicting results. This study aimed to compare the long-term outcomes between patients with LS and SCRC. Methods Between June 2008 and September 2018, a total of 47 patients were diagnosed with LS by genetic testing at Fudan University Shanghai Cancer Center. A 1:2 propensity score matching was performed to obtain homogeneous cohorts from SCRC group. Thereafter, 94 SCRC patients were enrolled as control group. The long-term survival rates between the two groups were compared, and the prognostic factors were also analyzed. Results The 5-year OS rate of LS group was 97.6%, which was significantly higher than of 82.6% for SCRC group (p = 0.029). The 5-year PFS rate showed no significant differences between the two groups (78.0% for LS group vs. 70.6% for SCRC patients; p = 0.262). The 5-year TFS rates in LS group was 62.1% for LS patients, which were significantly lower than of 70.6% for SCRC group (p = 0.039). By multivariate analysis, we found that tumor progression of primary CRC and TNM staging were independent risk factors for OS. Conclusion LS patients have better long-term survival prognosis than SCRC patients. Strict regular follow-up monitoring, detection at earlier tumor stages, and effective treatment are key to ensuring better long-term prognosis.

show abstract

Section: Discussionsupporting

confidence: 85%

Comparison of Long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis

Liu

Zheng

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A number of factors could underlie inter-tumoral heterogeneity of TILs among dMMR tumors including differences in the overall mutation burden, unstable microsatellites, or variability in neoantigen profiles (36). A recent study found that MSI CRCs from patients with Lynch Syndrome (n=85) had a higher density of CD3 + TILs in association with more somatic mutations, higher neoantigen burden, and better survival compared to sporadic-MSI CRCs (n=67) (37). Recent analysis of cancer exomes in 18 cancer types found a correlation between survival outcomes and the overall burden of unstable microsatellites, suggesting that MSI may be more informative when analyzed as a continuous rather than a discrete phenotype (38).…”

Section: Discussionmentioning

confidence: 99%

Intertumoral Heterogeneity of CD3+ and CD8+ T-Cell Densities in the Microenvironment of DNA Mismatch-Repair–Deficient Colon Cancers: Implications for Prognosis

Yoon

Shi

Heying

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

Background: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared to MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n=278; pMMR, n=283) from a phase 3 adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: While CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR vs pMMR tumors overall, inter-tumoral heterogeneity in densities between tumors was significantly higher by 30–88% among dMMR vs pMMR cancers (P<.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs high) CD3+IM was independently associated with poorer OS among dMMR (HR 4.76 [95% CI 1.43–15.87]; P=.0019) and pMMR tumors (P=.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater inter-tumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

show abstract

“…he TIL density (CD3 + , CD4 + , CD8 + , and FOXP3 + T reg ) is prominent in MSI tumors relative to MSS tumors [31,53] and CD8 + and CD3 + , but not FOXP3, and TIL densities correlate well with the percentage of frameshift mutations detected in MSI tumors [54]. Among MSI mCRC cases, tumors in Lynch-associated patients show increased TIL infiltration (CD3 + , CD8 + , or T reg ) and higher TMB (median 384 vs. 71) compared to sporadic patients [55]. The quantification of T cells and cytotoxic T cells (CD3 and CD8) in mCRC tumors (immunoscore) shows that a higher immunoscore correlates with a decreased likelihood of metastasis [56] and can also predict overall survival [57].…”

Section: Immune Microenvironments In Crcmentioning

confidence: 99%

The Tumor Microenvironment in Colorectal Cancer Therapy

Pedrosa

Espósito

Thomson

et al. 2019

Cancers

View full text Add to dashboard Cite

The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies bevacizumab and aflibercept, for the management of mCRC over a decade ago, extensive efforts have been devoted to discovering predictive factors of the anti-angiogenic response, unsuccessfully. Recent evidence has suggested a potential correlation between angiogenesis and immune phenotypes associated with colorectal cancer. Here, we review evidence of interactions between tumor angiogenesis, the immune microenvironment, and metabolic reprogramming. More specifically, we will highlight such interactions as inferred from our novel immune-metabolic (IM) signature, which groups mCRC into three distinct clusters, namely inflamed-stromal-dependent (IM Cluster 1), inflamed-non stromal-dependent (IM Cluster 2), and non-inflamed or cold (IM Cluster 3), and discuss the merits of the IM classification as a guide to new immune-metabolic combinatorial therapeutic strategies in mCRC.

show abstract

The Heterogeneity Between Lynch-Associated and Sporadic MMR Deficiency in Colorectal Cancers

Abstract: There are heterogeneities in dMMR CRCs. Lynch-associated dMMR patients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger immunoreactions and survival improvement.

Cited by 39 publications

References 40 publications

Comparison of Long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis

Comparison of Long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis

Intertumoral Heterogeneity of CD3+ and CD8+ T-Cell Densities in the Microenvironment of DNA Mismatch-Repair–Deficient Colon Cancers: Implications for Prognosis

The Tumor Microenvironment in Colorectal Cancer Therapy

Contact Info

Product

Resources

About