M2-PK
Tumour Pyruvate Kinase M2
What it is
Pyruvate kinase M2 (PKM2) is an isoform of the glycolytic enzyme pyruvate kinase that is expressed at high levels in proliferating cells. In most differentiated adult tissues, the tetrameric (active) form of pyruvate kinase predominates, efficiently converting phosphoenolpyruvate to pyruvate and channelling glucose metabolism toward oxidative phosphorylation. In cancer cells and other rapidly dividing cells, the dimeric (M2) form accumulates — and this dimeric form is catalytically less active, causing a metabolic shift that diverts glycolytic intermediates toward biosynthetic pathways (nucleotide synthesis, lipid synthesis, amino acid production) to support rapid cell proliferation. This metabolic reprogramming is part of the Warburg effect. The dimeric M2-PK is shed from proliferating cells into the intestinal lumen and can be detected in stool (stool M2-PK) or in blood (plasma M2-PK). The Blueprint Bloodwork protocol uses stool M2-PK as a complementary colorectal cancer screening marker alongside FIT.
Why we measure it
The key limitation of FIT is that it detects only bleeding lesions. Colorectal adenomas and some early cancers bleed intermittently or not at all — a non-haemorrhagic lesion, even a large adenoma, can produce a negative FIT result on any given annual test. M2-PK addresses this gap by detecting the metabolic signature of proliferating cells rather than haemorrhage — it is elevated in the stool from polyps and cancers that are not producing enough blood to trigger a positive FIT. Several clinical studies have found that stool M2-PK has sensitivity for colorectal cancer of approximately 80–85%, with reasonable specificity, and that combining FIT and M2-PK detects more colorectal adenomas and cancers than FIT alone — without substantially increasing the false-positive rate. The combination is synergistic because the two markers detect partially non-overlapping populations: FIT catches bleeding lesions; M2-PK catches metabolically active lesions. A positive result on either marker triggers colonoscopy referral; together they provide a more complete non-invasive screen.
Why every 12 months
Annual stool M2-PK testing is appropriate alongside annual FIT. Like FIT, M2-PK is collected from a home stool sample and returned for laboratory analysis. Both tests are coordinated within the Blueprint Bloodwork annual cycle.
What movement means
Stool M2-PK results are typically reported as a quantitative value in Units/mL (U/mL), with a positivity threshold defined by the manufacturer and laboratory. Common positivity thresholds are in the range of 4 U/mL. A positive stool M2-PK triggers the same clinical pathway as a positive FIT — colonoscopy referral.
Negative
< 4 U/mL (threshold varies by laboratory)
Below the positivity threshold. Combined with a negative FIT, provides reassurance of low colorectal cancer risk for the current annual cycle. Annual retesting is appropriate.
Shastri YM et al., Alimentary Pharmacology & Therapeutics, 2006
Positive
≥ 4 U/mL (threshold varies by laboratory)
Above the positivity threshold. Indicates the presence of metabolically active proliferating cells in the lower GI tract. Colonoscopy referral is recommended. A positive M2-PK combined with a negative FIT suggests a non-haemorrhagic lesion — metabolically active but not yet bleeding — which is clinically significant.
Shastri YM et al., Alimentary Pharmacology & Therapeutics, 2006
References
- 1.
Shastri YM, Naumann M, Oremek GM, et al.. “Prospective Multicenter Evaluation of Fecal Tumor Pyruvate Kinase Type M2 (M2-PK) as a Screening Biomarker for Colorectal Neoplasia.” International Journal of Cancer. 2006.
- 2.
Hardt PD, Toepler M, Ngoumou B, Rupp J, Kloer HU. “Measurement of Fecal Pyruvate Kinase Type M2 (Tumor M2-PK) Concentrations in Patients with Gastric Cancer, Colorectal Cancer, Colorectal Adenomas and Controls.” Anticancer Research. 2003.
- 3.
Christopoulos C, Kalogeropoulos N. “Pyruvate Kinase M2 as a Biomarker of Colorectal Cancer Screening.” World Journal of Gastrointestinal Oncology. 2019.
- 4.
Vander Heiden MG, Cantley LC, Thompson CB. “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation.” Science. 2009.