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

Authors: Steven M. Blum MD1,2, William R. Jeck MD, PhD3,4, Lindsay Kipnis MS, LGC1, Ronald Bleday MD3,5, Jonathan A. Nowak MD, PhD1,3,5, and Matthew B. Yurgelun MD1,3,5
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  • 1 Dana-Farber Cancer Institute,
  • | 2 Massachusetts General Hospital, and
  • | 3 Brigham & Women’s Hospital, Boston, Massachusetts;
  • | 4 Duke University School of Medicine, Durham, North Carolina; and
  • | 5 Harvard Medical School, Boston, Massachusetts.

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.

Familial adenomatous polyposis (FAP) and Lynch syndrome embody the 2 major molecular pathways of colorectal carcinogenesis: chromosomal instability (CIN) and microsatellite instability (MSI), respectively.1,2 CIN and MSI are typically considered to be mutually exclusive biologic mechanisms. The identification of tumors driven by the MSI pathway has significant therapeutic implications, because colorectal cancers (CRCs) driven by this mechanism respond to immune checkpoint inhibitors (ICIs), whereas tumors driven by the CIN pathway do not.3 This report presents a case involving a young woman with FAP who was treated for medulloblastoma as a child and developed MSI-high colon cancer as a young adult. Her case highlights the possibility for overlap between the CIN and MSI carcinogenic pathways and its potential clinical ramifications.

Case Report

In December 2018, a 24-year-old woman presented to our institution with severe iron deficiency anemia and rectal bleeding. Her medical history was notable for medulloblastoma treated at the age of 6 years with craniospinal irradiation at a total dose of 2,340 cGy and chemotherapy with lomustine, vincristine, and cisplatin. These treatments left her with growth hormone deficiency, hypothyroidism, ataxia, and mild neurocognitive impairment. She also has a history of a benign chest wall desmoid tumor.

As part of her workup for rectal bleeding, esophagogastroduodenoscopy was performed, which revealed numerous small fundic gland polyps. Colonoscopy identified a large rectal tubulovillous adenoma, numerous small and large adenomas in the sigmoid colon, and an obstructing mass at 38 cm from the anal verge, biopsy of which was nondiagnostic. Imaging (Figure 1A) revealed a lobulated, mucin-containing mass arising from the sigmoid colon with invasion of the bladder and cecum. However, she did not have evidence of distant metastases. Germline genetic testing performed on peripheral blood using a commercial 47-gene panel (Invitae Corp) revealed a pathogenic APC c.3180_3184delAAAAC (p.Q1062*) variant (supplemental eTable 1, available with this article at JNCCN.org). No germline variants were identified in the other 46 genes examined, including the mismatch repair genes, and germline testing of her parents and siblings has not yet been performed. The patient has no known family history of malignancy or polyposis in her parents, siblings, or other more distant relatives. Surgical exploration in February 2019 revealed a perforated sigmoid colon mass with an abscess cavity involving the bladder, cecum, and terminal ileum. A total colectomy with end ileostomy and Hartmann’s pouch were performed with incomplete resection of gross tumor at the bladder dome.

Figure 1.
Figure 1.
Figure 1.

Radiographic and pathologic correlates from a case of microsatellite instability-high colon cancer in a woman with familial adenomatous polyposis. (A) MRI of the pelvis at the time of diagnosis showing a mass arising from the sigmoid colon and invading the bladder. (B) MRI of the pelvis after combined therapy with ipilimumab and nivolumab showing evidence of a response. (C) Sigmoid colon resection specimen with pT4b adenocarcinoma (bracket) and numerous polyps (arrows).

Citation: Journal of the National Comprehensive Cancer Network 19, 12; 10.6004/jnccn.2021.7073

Pathologic examination revealed an 8.8-cm, perforated, moderately differentiated mucinous adenocarcinoma arising from the sigmoid colon with direct extension into the cecum, small bowel, and associated abscess cavity (pT4b) (Figure 1C, D). Nineteen tubular adenomas were identified in the colectomy specimen, and a second focus of pT1 mucinous adenocarcinoma was identified in association with a sigmoid colon adenoma (Figure 1E, F). At gross examination, the polyp-containing carcinoma was grossly distinct from the invasive tumor, with intervening normal mucosa and no underlying connection between the 2 lesions. None of 62 lymph nodes were involved with carcinoma (pN0). Immunohistochemistry revealed absent expression of MSH2 and MSH6 (with intact expression of MLH1 and PMS2) in both the pT4b (Figure 1G) and pT1 adenocarcinomas (Figure 1H), whereas expression of all proteins was intact in nonneoplastic cells.

Somatic genetic analyses of both the pT4b and pT1 tumors was performed using exonic sequencing of 447 cancer genes and rearrangement detection from 191 regions across 60 genes, as previously described (Table 1, supplemental eTable 1).4,5 Somatic mutations are determined by a bioinformatics pipeline intended to remove likely germline variants present in local patient populations and public databases.6,7 This analysis identified the known germline APC variant; another pathogenic APC variant, c.4660_4661insA (p.T1556N*3); a pathogenic MSH2 variant, c.560delT (p.E188Rfs*26); and other somatic variants shared between the 2 tumors (supplemental eTable 2, supplemental eFigure 1). The pT1 cancer harbored a third pathogenic somatic APC variant (c.4461delT [p.L1488Yfs*19]) not seen in the pT4b tumor, whereas the pT4b cancer harbored a somatic APC variant of uncertain significance (c.775C>T [p.R259W]) not seen in the pT1 tumor. In both tumors, the only significant copy number alteration identified was a deletion of 2p16.3-p22.1, inclusive of the entire EPCAM, MSH2, and MSH6 genes (Figure 1I, J). Both tumors were MSI-high with markedly high tumor mutational burdens.

Table 1.

Summary of Somatic Sequencing Results

Table 1.

Because the patient had gross residual disease, the decision was made to treat her with FOLFOX (5-FU/leucovorin/oxaliplatin) chemotherapy to potentially reduce her tumor burden and enable completion of resection of her remaining cancer. She received eight 14-day cycles of FOLFOX, with mild progression of the residual pelvic mass seen on imaging. Because of the MSI-high biology, treatment was changed to ipilimumab, 1 mg/kg and nivolumab, 3 mg/kg for four 21-day cycles, followed by 2 doses of nivolumab, 240 mg monotherapy administered 14 days apart.8 Repeat imaging showed an excellent response to therapy but a large residual mass (Figure 1B), so the patient underwent en bloc resection with Hartmann’s pouch resection, partial cystectomy, partial hysterectomy, and unilateral salpingo-oophorectomy in November 2019. Pathologic evaluation identified a 6.2-cm tumor bed consisting predominantly of mucin with only minute microscopic foci of residual adenocarcinoma and negative margins. CT imaging performed 4 and 10 months later showed no evidence of recurrent/metastatic disease.

Discussion

Hereditary cancer syndromes can offer critical insights into the pathobiology of human oncogenesis.9 In this case, the unique finding of MSI-high in FAP-associated colon cancer shows the potential for overlap between the CIN and MSI carcinogenic pathways, which are typically considered to be mutually exclusive.2,10,11 The overlapping CIN and MSI biologies had clinical relevance for this individual, as evidenced by the profound response to ICI therapy leading to an eventual R0 resection. Data have consistently shown ICIs to be highly effective treatments for MSI-high CRCs,3,8,12 whereas those arising through the CIN pathway do not benefit from immune checkpoint blockade.3

Intriguingly, this individual’s pT1 adenocarcinoma was also MSI-high with identical oncogenic mutations in MSH2, KRAS, and PIK3CA and numerous shared variants presumed to be “passenger” mutations from the underlying MSI. One notable exception, however, is that this pT1 adenocarcinoma had a third inactivating c.4461delT APC variant that was not seen in the pT4b adenocarcinoma, suggesting that this pT1 cancer may have actually represented a metastasis from the dominant pT4b cancer to a nearby adenoma.

Based on the available germline and somatic data, we hypothesize that this patient’s dominant pT4b adenocarcinoma arose from a traditional FAP adenoma with biallelic APC inactivation and somatic mutational activation of KRAS. Although the patient’s family has not yet completed germline sequencing, the lack of a family history of colon cancer or polyps leads us to believe that she has a de novo germline mutation in APC, which occurs in approximately one-third of FAP cases.1 Given the paucity of other chromosomal copy number alterations, however, we hypothesize that the large chromosome 2p16.3-p22.1 deletion (inclusive of EPCAM, MSH2, and MSH6) was an early molecular event in this cancer that led to expansion of an MSI-high clone, rather than a CIN cancer, and subsequent hypermutation after acquisition of a somatic c.560delT “second hit” in MSH2. Interestingly, recent case series of Hodgkin lymphoma survivors have suggested that treatment-induced CRCs are disproportionately MSI-high with somatic biallelic mismatch repair gene inactivation.13,14

Conclusions

Although we are only able to speculate regarding the process through which this individual with FAP developed MSI-high cancer, this case provides novel insight about the potential for intersection between CIN and MSI colorectal carcinogenesis. Such biology is of critical therapeutic relevance because of the efficacy of immune checkpoint blockade for MSI-driven cancers, and this case further supports the importance of testing for MSI status in all cases of CRC, as suggested by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).15 Interestingly, this patient’s experience suggests that MSI-high biology and vulnerability to checkpoint blockade can emerge even in the setting of conditions that can predispose patients to other, theoretically distinct pathways of carcinogenesis. Finally, the study highlights the critical importance of screening survivors of childhood malignancies for secondary cancers and the opportunities to learn about how therapeutic interventions may impact survivorship.

References

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    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.

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

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    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.

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

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    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.

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    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.

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    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.

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    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.

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

  • View in gallery View in gallery

    Radiographic and pathologic correlates from a case of microsatellite instability-high colon cancer in a woman with familial adenomatous polyposis. (A) MRI of the pelvis at the time of diagnosis showing a mass arising from the sigmoid colon and invading the bladder. (B) MRI of the pelvis after combined therapy with ipilimumab and nivolumab showing evidence of a response. (C) Sigmoid colon resection specimen with pT4b adenocarcinoma (bracket) and numerous polyps (arrows).

  • 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/

    • 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
    • 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
    • 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.

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