HSPH1 – Colorectal Cancer

HSPH1, which encodes the heat shock protein HSP110, has emerged as a significant candidate in the predisposition to colorectal cancer. Multiple independent studies have investigated its role by evaluating both genetic alterations and downstream functional effects. This summary integrates evidence from case series, multi‐patient studies, and functional assessments to provide clinicians and researchers with a comprehensive overview of the HSPH1–colorectal cancer association (PMID:30683709).

The clinical validity of this association is supported by recurrent observations of potential loss‑of‑function alterations in HSPH1 in colorectal cancer patients. Although detailed familial segregation data are limited, case series in young patients and candidate gene approaches have consistently implicated HSPH1, suggesting an autosomal dominant pattern. The genetic evidence, though derived from a moderate number of probands, points to a contributory role in disease predisposition (PMID:25219767, PMID:30683709).

Genetic investigations have revealed that alterations in HSPH1 are present in patients with early‑onset colorectal cancer. While the reported studies do not provide extensive segregation data—in this context, zero additional affected relatives were explicitly documented—the recurrent detection of HSPH1 variants across independent cohorts strengthens the evidence for a causative link. This genetic evidence supports a moderate rating for the gene–disease association from the perspective of variant occurrence and case series findings.

Functional studies further underscore the pathogenic role of HSPH1 in colorectal cancer. A series of in vitro and in vivo experiments have demonstrated that HSP110 (the protein product of HSPH1) modulates key cellular processes including chaperone activity, DNA repair, and the shift in macrophage polarization toward a pro‑tumor phenotype. For instance, phosphorylation at Ser509 has been shown to alter its inhibitory effect on HSP70‑mediated protein folding, while nuclear translocation upon genotoxic stress facilitates DNA repair mechanisms essential for cell survival under chemotherapy stress (PMID:12558502, PMID:30542121).

The converging genetic and functional data yield a coherent narrative linking HSPH1 alterations to colorectal tumorigenesis. In addition to the inherent role in protein folding and stress response, the aberrant activity of HSPH1 demonstrably impacts key oncogenic pathways. This provides a mechanistic rationale for its involvement in modulating both disease onset and chemotherapeutic response, thereby informing diagnostic decision‑making and potential therapeutic strategies.

Key take‑home: The integration of moderate genetic evidence with strong functional data establishes HSPH1 as a clinically relevant gene in colorectal cancer, underscoring its value as a biomarker for risk assessment and treatment planning.

References

• The oncologist • 2019 • Suspected Hereditary Cancer Syndromes in Young Patients: Heterogeneous Clinical and Genetic Presentation of Colorectal Cancers. PMID:30683709
• Oncoimmunology • 2016 • Extracellular HSP110 skews macrophage polarization in colorectal cancer. PMID:27622020
• Oncogene • 2019 • HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells. PMID:30542121
• The Biochemical journal • 2003 • Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. PMID:12558502
• Cellular and molecular life sciences : CMLS • 2022 • Consequences of the Hsp110DE9 mutation in tumorigenesis and the 5‑fluorouracil‑based chemotherapy response in Msh2‑deficient mice. PMID:35648235
• Nature medicine • 2011 • Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. PMID:21946539

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