Kisho is an information platform, not a medical provider. Nothing on this site constitutes medical advice, diagnosis, or treatment recommendations. All content is aggregated from publicly available sources (including ClinicalTrials.gov, PubMed, FDA.gov, and Orphanet) and is provided for informational purposes only. Clinical trial eligibility, treatment decisions, and any health-related actions should always be discussed with a qualified healthcare professional. Kisho does not endorse any specific therapy, organization, or clinical trial. Terms of use · Privacy policy
An instance of prostate cancer that is caused by an inherited genomic modification in an individual. Familial prostate cancer (FPC) is a malignant tumor of the prostate with an early onset. FPC is either asymptomatic or causes mictionary symptoms, erectile dysfunction, bone pain, venous compression and infectious or inflammatory syndrome (for the metastatic forms). It is also characterized by familial antecedents.
Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.
Features include: Prostate cancer.
GeneReviews
Clinical Guidance
CHEK2-related cancer predisposition is predominantly characterized by an increased risk of female breast cancer and contralateral breast cancer . To a lesser extent there is an association with prostate cancer . Associations for other cancers are less well established or conflicting. Notably, cancer risks can vary considerably depending on modifying factors such as family history. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. Cancer Risk in CHEK2 Heterozygotes Compared to General Population Risk
Genetic Landscape
Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.
CHEK2
CHEK2 encodes checkpoint kinase 2 (543 aa). Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. Highest expression in Nerve Tibial (14.6 TPM) and Cells EBV-transformed lymphocytes (14.5 TPM).
Prostate cancer, hereditary is associated with mutations in the CHEK2 gene on chromosome 22.
The CHEK2 protein participates in CHEK2 is recruited to DNA DSBs pathway.
CHEK2 is classified as a druggable target (Clinically Actionable, Druggable Genome, Enzyme, Kinase, Serine Threonine Kinase, and Transcription Factor categories) with score 1.2.
KLF6
KLF6 encodes KLF transcription factor 6 (283 aa). Transcriptional activator. Binds a GC box motif. Could play a role in B-cell growth and development Highest expression in Nerve Tibial (264.7 TPM) and Skin Not Sun Exposed Suprapubic (249.8 TPM).
Diagnosis
Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.
GeneReviews
Diagnostic Criteria
Suggestive Findings
CHEK2-related cancer predisposition should be suspected in probands with the following clinical findings, family history, and/or laboratory findings.
Clinical findings
Estrogen receptor (ER)-positive breast cancer, particularly young onset and/or bilateral breast cancer in a proband with a family history of breast cancer in close relatives
Treatment
Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.
No approved treatments are currently available for prostate cancer, hereditary. The disease remains an area of unmet medical need.
GeneReviews
Management Guidelines
Clinical management recommendations for CHEK2 heterozygotes were published by an international working group . The report advised that, when possible, recommendations should be guided by personalized risk estimates, particularly with respect to recommendations for breast surveillance, and in accordance with country-specific guidelines.
Evaluations Following Initial Diagnosis
Prognosis
Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.
GeneReviews
Surveillance Guidelines
To monitor existing manifestations and the emergence of new manifestations, the evaluations summarized in are recommended for all individuals with a heterozygous CHEK2 pathogenic variant.
Table 4.
CHEK2-Related Cancer Predisposition: Recommended Surveillance
System/Concern | Evaluation | Comment
Breast cancer (in females)1
Research Landscape
Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.
3 clinical trials registered. Interventions under study include other interventions. Pipeline includes 2 NA. Research is primarily sponsored by academic and government institutions.
6 publications have been identified in PubMed for prostate cancer, hereditary. Research spans Epidemiology / Natural History (83%) and Case Report / Case Series (17%).
Recent Publications
Park JE (2026). [PMID: 40956513](https://pubmed.ncbi.nlm.nih.gov/40956513/). *Breast Cancer*. [Epidemiology / Natural History]
Diseases are connected by shared genes, phenotypes, therapeutic targets, and MONDO disease hierarchy. The Rare badge reflects Kisho's rarity classification — scored from authoritative sources including OMIM, Orphanet, orphan drug designations, clinical trial activity, and published prevalence data.
Cumulative lifetime risk figures not published 1. 2. 3. 4. Breast cancer. Large case-control studies have reported an increased risk of breast cancer for females heterozygous for the germline CHEK2 pathogenic variant , with an odds ratio (OR) of 2.66 (95% confidence interval [CI]: 2.27-3.11).
Prostate cancer, hereditary is associated with mutations in the KLF6 gene on chromosome 10.
KLF6 is classified as a druggable target (Transcription Factor category) with score 0.0.
MAD1L1
MAD1L1 encodes mitotic arrest deficient 1 like 1 (718 aa). Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. Highest expression in Testis (18.9 TPM) and Cells EBV-transformed lymphocytes (16.0 TPM).
Prostate cancer, hereditary is associated with mutations in the MAD1L1 gene on chromosome 7.
MAD1L1 is classified as a druggable target with score 0.6.
MXI1
MXI1 encodes MAX interactor 1, dimerization protein (228 aa). Transcriptional repressor. MXI1 binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5'-CAC[GA]TG-3'. Highest expression in Artery Tibial (141.3 TPM) and Esophagus Muscularis (109.7 TPM).
Prostate cancer, hereditary is associated with mutations in the MXI1 gene on chromosome 10.
MXI1 is classified as a druggable target (Transcription Factor category) with score 5.0.
PTEN
PTEN function has not been fully characterized.
Prostate cancer, hereditary is associated with mutations in the PTEN gene on chromosome 10.
ZFHX3
ZFHX3 function has not been fully characterized.
Prostate cancer, hereditary is associated with mutations in the ZFHX3 gene on chromosome 16.
GeneReviews
Clinical Guidance
Cancer risk estimates for CHEK2 heterozygotes with missense variants have been reported to be lower than estimates for CHEK2 truncating variants in some studies . A large study from BRIDGES estimated an OR 1.5 (OR = 1.42, 95% CI: 1.28-1.58, P= 2.5 1011) for rare missense variants (defined as variants with a population frequency of 0.001) and found no correlation with the variant position in the gene, while the OR for truncating variants was 2.66 (95% CI: 2.27-3.11) . However, genotype-phenotype correlations have been difficult to determine due to inclusion of low-penetrance missense variants in studies of cancer risk, thus influencing the risk for missense variants as a whole.
The penetrance of breast and other cancers associated with pathogenic variants in CHEK2 is typically in the range of 20%-30%, but overall individual lifetime risk can be lower or higher when modifying factors are taken into consideration. CHEK2 is considered a moderate risk or intermediate penetrance cancer predisposition gene (see for associated cancer risks).
Prostate cancer, particularly in a proband with a family history of prostate and/or breast cancer
Results from a risk assessment model incorporating family history, personal risk factors, ER status of breast cancer, and breast cancer diagnoses in a family indicates an increased likelihood of identifying a CHEK2 pathogenic variant (e.g., CanRisk)
Syndromic breast cancer. Individuals with the cancer susceptibility syndromes listed in have an elevated breast cancer risk and may have features overlapping those associated with CHEK2-related cancer predisposition (e.g., Estrogen receptor (ER)-positive breast cancer and moderate family history). It is not possible to distinguish CHEK2-related cancer predisposition from these other cancer susceptibility syndromes based solely on the constellation of tumors and ages of cancer onset present in the family. In all individuals, molecular genetic testing is necessary to fully differentiate the disorders. Table 3. Genes Associated with Cancer Susceptibility to Consider in the Differential Diagnosis of CHEK2-Related Cancer Predisposition
Gene(s)
Cancer Susceptibility Syndrome
MOI
Associated Cancers/ Distinctive Features
ATM
ATM-related cancer susceptibility (c.7271TG)
AD
Specific ATM pathogenic variants (e.g., c.7271TG) are assoc w/high-penetrance breast cancer; heterozygosity for most other ATM pathogenic variants is assoc w/moderate-penetrance breast cancer.1 BRCA1 BRCA2
BRCA1- BRCA2-assoc hereditary breast ovarian cancer
AD
Breast ovarian cancer, predominantly young onset; Assoc w/triple-negative breast cancer (BRCA1) CDH1
—
Hereditary diffuse gastric cancer
AD
Breast cancer (lobular); Diffuse gastric cancer; Majority of cancers occur age 40 yrs
—
PALB2
PALB2-related cancer susceptibility (OMIM 620442)
AD
High-penetrance breast cancer2; Ovarian cancer; Male breast cancer; Pancreatic cancer PTEN
PTEN hamartoma tumor syndrome
AD
Breast cancer; Other cancers: thyroid, RCC, endometrial, colorectal; Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules; Affected persons usually present by late 20s. STK11
—
Peutz-Jeghers syndrome
AD
Breast cancer; Other cancers: GI, ovarian (mostly SCTAT), cervical (adenoma malignum), pancreatic, Sertoli cell testicular; GI polyposis, mucocutaneous pigmentation, hyperpigmented macules on fingers TP53
—
Li-Fraumeni syndrome
AD
Breast cancer (often premenopausal); Other cancers: soft tissue sarcoma, osteosarcoma, brain, adrenocortical carcinoma, leukemias; Early onset multiple primary cancers Moderate-penetrance (moderate-risk) genes for breast cancer
—
ATM
ATM-related cancer susceptibility1
AD
Specific ATM pathogenic variants, most notably c.7271TG, are assoc w/high-penetrance breast cancer; heterozygosity for most other ATM pathogenic variants is assoc w/moderate-penetrance breast cancer.; risk for other types of tumors such as pancreatic cancer prostate cancer1
BARD1
BARD1-related cancer susceptibility (OMIM 114480)
AD
Breast cancer
RAD51C
RAD51C-related cancer susceptibility (OMIM 613399)
Genetic testing for CHEK2, KLF6, MAD1L1, MXI1, PTEN, ZFHX3 is available. Testing is considered confirmatory for diagnosis.
Individuals who have a germline pathogenic variant in CHEK2 are counseled at the time of disclosure of molecular genetic test results about their options for and .
Treatment of Manifestations
At present there is insufficient evidence to recommend specific cancer treatment based on identification of CHEK2-related cancer predisposition. Standard cancer treatments are recommended. Breast cancer. In those with breast cancer, risk-reducing contralateral mastectomy is generally not recommended but may be considered in some situations. This should only be undertaken following a personalized risk assessment, utilizing a model such as CanRisk that incorporates personal and family risk factors and considers remaining lifetime contralateral breast cancer (CBC) risk, alongside factors not assessed by CanRisk such as competing risk from the primary breast cancer diagnosis and potential risk reduction from endocrine treatment, given that the majority of breast cancers in individuals with a heterozygous CHEK2 pathogenic variant are estrogen receptor (ER) positive.
A number of ongoing studies are investigating novel approaches to the treatment of CHEK2-associated breast and prostate cancer. The majority of these studies involve poly [ADP-ribose] polymerase (PARP) inhibitors. However, to date there is insufficient evidence to recommend specific cancer treatment based on identification of CHEK2-related cancer predisposition. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies.
| Breast self-exam training | At time of identification of CHEK2 pathogenic variant
Mammogram | Every 12 mos beginning at age 40 yrs
Breast MRI2 | • NCCN guidelines (US): Consider annually from age 30-35 yrs in those w/strong family history, other risk factors (e.g., age, breast density), preference of affected person.3
UK: Consider annually from age 30 yrs based on personal risk assessment w/CanRisk demonstrating lifetime breast cancer risk ≥40%4 in conjunction w/specific 10-yr age-related risks.5
Prostate cancer (in males)
| Serum PSA | NCCN: Consider annually beginning at age 40 yrs esp in those w/strong family history of prostate cancer (e.g., ≥2 affected relatives, early onset, or metastatic disease) using shared decision-making process.3
Other cancers
| To date, there are no recommendations for enhanced surveillance for other cancers. Note: NCCN recommends general population screening for CRC in those w/CHEK2 cancer predisposition.3
CRC = colorectal cancer; MOI = mode of inheritance; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen
Radiopharm Theranostics received a positive recommendation from the Data Safety and Monitoring Committee to advance to Cohort 4 in the Phase 1 HEAT clinical trial for 177Lu-RAD202. This trial is part of their innovative pipeline targeting various solid tumor cancers, including lung, breast, and prostate cancers.
A multicenter study analyzed the effectiveness of stereotactic radiotherapy for rib metastases from prostate cancer, focusing on local control, pain response, and treatment tolerance. The findings contribute to understanding treatment options for patients with metastatic prostate cancer.
A study identifies subclonal complete loss of CDKN1B as a prevalent genomic alteration in prostate cancer, highlighting its associations with race and patient outcomes. This discovery may inform future research and treatment strategies in prostate cancer management.
A case report highlights penile metastasis from castration-resistant prostate cancer, providing insights into this rare occurrence. This study contributes to the understanding of metastatic patterns in advanced prostate cancer.
Pfizer presented several late-breaking data at ASCO, highlighting advancements in lung, colorectal, and prostate cancer. However, the most significant results are anticipated later this year.
