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Prognostic Significance and Molecular Features of Signet-Ring Cell and Mucinous Components in Colorectal Carcinoma

  • Colorectal Cancer
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Abstract

Background

Colorectal carcinoma (CRC) represents a group of histopathologically and molecularly heterogeneous diseases, which may contain signet-ring cell component and/or mucinous component to a varying extent under pathology assessment. However, little is known about the prognostic significance of those components, independent of various tumor molecular features.

Methods

Utilizing a molecular pathological epidemiology database of 1,336 rectal and colon cancers in the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined patient survival according to the proportion of signet-ring cell and mucinous components in CRCs. Cox proportional hazards models were used to compute hazard ratio (HR) for mortality, adjusting for potential confounders including stage, microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations.

Results

Compared to CRC without signet-ring cell component, 1–50 % signet-ring cell component was associated with multivariate CRC-specific mortality HR of 1.40 [95 % confidence interval (CI) 1.02–1.93], and >50 % signet-ring cell component was associated with multivariate CRC-specific mortality HR of 4.53 (95 % CI 2.53–8.12) (P trend < 0.0001). Compared to CRC without mucinous component, neither 1–50 % mucinous component (multivariate HR 1.04; 95 % CI 0.81–1.33) nor >50 % mucinous component (multivariate HR 0.82; 95 % CI 0.54–1.23) was significantly associated with CRC-specific mortality (P trend < 0.57).

Conclusions

Even a minor (50 % or less) signet-ring cell component in CRC was associated with higher patient mortality, independent of various tumor molecular and other clinicopathological features. In contrast, mucinous component was not associated with mortality in CRC patients.

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Acknowledgment

We deeply thank hospitals and pathology departments throughout the United States for generously providing us with tissue specimens. In addition, we would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY.

Disclosure

The authors declare no conflict of interest.

Funding

This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969 to S.E. Hankinson; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S.F.; and R01 CA151993 to S.O.); and by grants from the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. K.I. was supported by a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and by Takashi Tsuruo Memorial Fund. S.A.K. is supported by an early exchange postdoctoral fellowship grant from Asan medical center. K.M. is supported by a fellowship grant from the Uehara Memorial Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Kentaro Inamura MD, PhD, Mai Yamauchi PhD, Reiko Nishihara PhD, Sun A Kim MD, PhD, Kosuke Mima MD, PhD, Yasutaka Sukawa MD, PhD, Tingting Li MD, Mika Yasunari BS, Jeffrey A. Meyerhardt MD, MPH, Charles S. Fuchs MD, MPH, Zhi Rong Qian MD, PhD & Shuji Ogino MD, PhD, MS

  2. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Kentaro Inamura MD, PhD & Curtis C. Harris MD

  3. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

    Reiko Nishihara PhD & Kana Wu MD, PhD

  4. Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing, China

    Tingting Li MD

  5. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

    Xuehong Zhang ScD, BMD & Charles S. Fuchs MD, MPH

  6. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Shuji Ogino MD, PhD, MS

  7. Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

    Shuji Ogino MD, PhD, MS

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  1. Kentaro Inamura MD, PhD
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  2. Mai Yamauchi PhD
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  3. Reiko Nishihara PhD
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  4. Sun A Kim MD, PhD
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  5. Kosuke Mima MD, PhD
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  6. Yasutaka Sukawa MD, PhD
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  8. Mika Yasunari BS
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  9. Xuehong Zhang ScD, BMD
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  10. Kana Wu MD, PhD
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  11. Jeffrey A. Meyerhardt MD, MPH
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  13. Curtis C. Harris MD
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  14. Zhi Rong Qian MD, PhD
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  15. Shuji Ogino MD, PhD, MS
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Corresponding authors

Correspondence to Kentaro Inamura MD, PhD or Shuji Ogino MD, PhD, MS.

Additional information

Kentaro Inamura, Mai Yamauchi, Reiko Nishihara, and Sun A Kim contributed equally. Curtis C. Harris, Zhi Rong Qian, and Shuji Ogino contributed equally.

Use of Standardized Official Symbols

We use HUGO (Human Genome Organisation)-approved official symbols for genes and gene products, including BRAF; KRAS; PIK3CA; all of which are described at www.genenames.org.

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Inamura, K., Yamauchi, M., Nishihara, R. et al. Prognostic Significance and Molecular Features of Signet-Ring Cell and Mucinous Components in Colorectal Carcinoma. Ann Surg Oncol 22, 1226–1235 (2015). https://doi.org/10.1245/s10434-014-4159-7

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