How many molecular subtypes? Implications of the unique tumor principle in personalized medicine

Ogino, Shuji; Fuchs, Charles S.; Giovannucci, Edward

doi:10.1586/erm.12.46

Cited by 155 publications

(144 citation statements)

References 105 publications

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“…Hence, heterogeneity actively influences the therapeutic tumor response and shapes drug resistance. In addition, the specific tumor microenvironment contributes to the uniqueness of each tumor lesion 26. Therefore, we used the tissue description and the tumor type reported for each iTL to develop a new classification of tumor lesions, based on the anatomical location and different reported features.…”

Section: The Cicil Methodologymentioning

confidence: 99%

Assessing Similarity Among Individual Tumor Size Lesion Dynamics: The CICIL Methodology

Terranova

Girard

Ιωάννου

et al. 2018

CPT Pharmacom & Syst Pharma

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Mathematical models of tumor dynamics generally omit information on individual target lesions (iTLs), and consider the most important variable to be the sum of tumor sizes (TS). However, differences in lesion dynamics might be predictive of tumor progression. To exploit this information, we have developed a novel and flexible approach for the non‐parametric analysis of iTLs, which integrates knowledge from signal processing and machine learning. We called this new methodology ClassIfication Clustering of Individual Lesions (CICIL). We used CICIL to assess similarities among the TS dynamics of 3,223 iTLs measured in 1,056 patients with metastatic colorectal cancer treated with cetuximab combined with irinotecan, in two phase II studies. We mainly observed similar dynamics among lesions within the same tumor site classification. In contrast, lesions in anatomic locations with different features showed different dynamics in about 35% of patients. The CICIL methodology has also been implemented in a user‐friendly and efficient Java‐based framework.

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Section: The Cicil Methodologymentioning

confidence: 99%

Assessing Similarity Among Individual Tumor Size Lesion Dynamics: The CICIL Methodology

Terranova

Girard

Ιωάννου

et al. 2018

CPT Pharmacom & Syst Pharma

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“…4,5 The complex interaction between an individual's genetic background and the environment has led to the concept of tumor uniqueness and molecular pathological epidemiology. 6 Current colorectal carcinoma classification largely reflects the polyp of origin for each group, various molecular pathways to neoplastic progression and molecular correlates with epidemiological features. Among the most commonly altered molecular pathways in colorectal carcinoma, the RAS-MAPK signaling pathway is deregulated in 55% of tumors, comprising mutually exclusive mutations in BRAF, KRAS and NRAS.…”

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confidence: 99%

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

et al. 2013

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KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O 6 -methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wildtype carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; Po0.001), demonstrated mucinous differentiation (46 vs 31%; P ¼ 0.001) and were associated with different MSI status (Po0.001) and with MGMT methylation (47 vs 21%; P ¼ 0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P ¼ 0.001), mucinous differentiation (46 vs 25%; Po0.001), presence of a contiguous polyp (38 vs 22%; Po0.001), MGMT methylation (47 vs 26%; P ¼ 0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P ¼ 0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P ¼ 0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

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“…[48][49][50][51][52][53] The importance of analyses of human tumor characteristics and host immunity has been increasing. 37,54 In fact, higher densities of CD3 C , CD8 C , and CD45RO C cells in colorectal cancer tissue have been associated with better prognosis, [38][39][40][41][42][43]55 suggesting antitumor effects of these T cells in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

et al. 2017

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Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3, or FOXP3 C cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3 C cell density (p trend D 0.006), but not with CD3C , CD8 C , or CD45RO C cell density (with the adjusted a level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3 C cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36-0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3 C cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.Abbreviations: ATP, adenosine triphosphate; CI, confidence interval; CIMP, CpG island methylator phenotype; FFPE, formalin-fixed paraffin-embedded; LINE-1, long interspersed nucleotide element-1; MSI, microsatellite instability;

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How many molecular subtypes? Implications of the unique tumor principle in personalized medicine

Cited by 155 publications

References 105 publications

Assessing Similarity Among Individual Tumor Size Lesion Dynamics: The CICIL Methodology

Assessing Similarity Among Individual Tumor Size Lesion Dynamics: The CICIL Methodology

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

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