A Case of Microsatellite Instability–High Colon Cancer in a Young Woman With Familial Adenomatous Polyposis

Authors:
Steven M. Blum Dana-Farber Cancer Institute,
Massachusetts General Hospital, and

Search for other papers by Steven M. Blum in
Current site
Google Scholar
PubMed
Close
 MD
,
William R. Jeck Brigham & Women’s Hospital, Boston, Massachusetts;
Duke University School of Medicine, Durham, North Carolina; and

Search for other papers by William R. Jeck in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Lindsay Kipnis Dana-Farber Cancer Institute,

Search for other papers by Lindsay Kipnis in
Current site
Google Scholar
PubMed
Close
 MS, LGC
,
Ronald Bleday Brigham & Women’s Hospital, Boston, Massachusetts;
Harvard Medical School, Boston, Massachusetts.

Search for other papers by Ronald Bleday in
Current site
Google Scholar
PubMed
Close
 MD
,
Jonathan A. Nowak Dana-Farber Cancer Institute,
Brigham & Women’s Hospital, Boston, Massachusetts;
Harvard Medical School, Boston, Massachusetts.

Search for other papers by Jonathan A. Nowak in
Current site
Google Scholar
PubMed
Close
 MD, PhD
, and
Matthew B. Yurgelun Dana-Farber Cancer Institute,
Brigham & Women’s Hospital, Boston, Massachusetts;
Harvard Medical School, Boston, Massachusetts.

Search for other papers by Matthew B. Yurgelun in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Two major molecular pathways of colorectal carcinogenesis, chromosomal instability (CIN) and microsatellite instability (MSI), are considered to be mutually exclusive. Distinguishing CIN from MSI-high tumors has considerable therapeutic implications, because patients with MSI-high tumors can derive considerable benefit from immune checkpoint inhibitors, and tumors that evolved through the CIN pathway do not respond to these agents. Familial adenomatous polyposis (FAP) is a genetic syndrome that is defined by a mutation in the APC gene and is thought to lead to carcinogenesis through the CIN pathway. Here, we report a case of a young woman with FAP who was treated for medulloblastoma as a child and developed advanced MSI-high colon cancer as a young adult. Her response to second-line immunotherapy enabled resection of her colon cancer, and she is free of disease >10 months after surgery. This case highlights the potential for overlap between the CIN and MSI carcinogenic pathways and associated therapeutic implications.

Submitted January 25, 2021; final revision received May 22, 2021; accepted for publication June 11, 2021.

Previous presentation: Preliminary data reported in this article were presented as a poster abstract at the 23rd Annual Meeting of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer; November 3–5, 2019; Salt Lake City, Utah.

Disclosures: Dr. Blum has disclosed serving as a consultant for Two River Consulting and Third Rock Ventures, and owning stock or having an ownership interest in Kronos Bio and Allogene Therapeutics. Dr. Yurgelun has disclosed receiving fees for peer review services from UpToDate. The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the Massachusetts General Hospital T32 grant from the NCI of the NIH under award number 2T32CA071345-21A1 (S.M. Blum).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Correspondence: Matthew B. Yurgelun, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1126, Boston, MA 02215. Email: matthew_yurgelun@dfci.harvard.edu

Supplementary Materials

    • Supplemental Materials (PDF 751 KB)
  • Collapse
  • Expand
  • 1.

    Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110:223262.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330337.

  • 3.

    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:25092520.

  • 4.

    Garcia EP, Minkovsky A, Jia Y, et al. Validation of OncoPanel a targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch Pathol Lab Med 2017;141:751758.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Nowak JA, Yurgelun MB, Bruce JL, et al. Detection of mismatch repair deficiency and microsatellite instability in colorectal adenocarcinoma by targeted next-generation sequencing. J Mol Diagn 2017;19:8491.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434443.

  • 7.

    National Heart, Lung, and Blood Institute Exome Sequencing Project. Exome Variant Server. Accessed May 18, 2021. Available at: https://evs.gs.washington.edu/EVS/

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773779.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science 1997;278:10431050.

  • 10.

    Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol 2011;6:479507.

  • 11.

    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759767.

  • 12.

    Andre T, Shiu K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study [abstract]. J Clin Oncol 2020;38(Suppl):Abstract LBA4.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Rigter LS, Snaebjornsson P, Rosenberg EH, et al. Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin’s lymphoma treatment. Gut 2018;67:447455.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Biller LH, Ukaegbu C, Dhingra TG, et al. A multi-institutional cohort of therapy-associated polyposis in childhood and young adulthood cancer survivors. Cancer Prev Res (Phila) 2020;13:291298.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Benson AB III, Venook AP, Al-Hawary MM, et al. Colon cancer, Version 2.2021. NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:329359.

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3970 391 53
PDF Downloads 1853 330 33
EPUB Downloads 0 0 0