Prostate cancer genetic testing

Many DNA genes play a role in hereditary prostate cancer including: BRCA 1, BRCA2, ATM, the mismatch repair of genes,  MLH1, MSH2, MSH6, PMS2, HOXB 13, PALB2, CHEK2.

BRCA1, ATM, CHEK 2, and PALB 2 are involved in homologous recombination DNA repair and are associated with increased prostate cancer risk.

Pathologic variants are more common in men with metastatic than low stage disease.

Germline pathogenic variants are present in 12 to 17% of patients with regional or metastatic disease.

Men with DNA repair and cancer susceptibility genes in Prostate cancer can inform disease management in men with non-aggressive prostate cancer, as men carrying deleterious variants in these genes, would likely develop advanced disease.

The percentage of patients with prostate cancer who have germline mutations in DNA repair genes ranges from 4.6% in localized prostate cancer to 11.8 to 16.2% in metastatic disease.

Germline, genetic testing is recommended for patients with clinically low to intermediate risk, localized disease, accompanied by family, history of prostate cancer, or high or very high risk, localized disease.

With regional distant metastasis being present, germline testing is recommended.

Hereditary prostate cancer accounts for 30 to 40% of early onset disease and more than 15% of patients with prostate cancer carry an identifiable pathogenic variant.

Patients with prostate cancer with pathogenic variants are at higher risk for progression during local therapy, metastasis, and have lower survival.

Patients  with BRCA1, BRCA2, or ATM mutations or eligible for treatment with PARP inhibitors.

Mutations in the homologous recombination repair pathway make tumor sensitive to PARP inhibition.

HOXB13 gene mutations are associated with a lifetime risk for prostate cancer that can be 8 to 10 times that of of the general population. 

HOXB13 gene mutations are associated with early onset of prostate cancer.

BRCA2 mutations are associated with a risk of prostate cancer 3 to 4 times that of the general male population, and are associated with more aggressive lesions, more advanced at the time of diagnosis, and poor prognosis.

BRCA1 mutations are associated with a higher risk of prostate cancer but not as high as with BRCA2 mutations.

Men with mutations in the BRCA1 or BRCA2 are at elevated risk for male breast cancer, pancreatic cancer, and melanoma. 

Women with these mutations are at elevated risk for female breast cancer, ovarian cancer, pancreatic cancer, and melanoma.

Mutations in DNA match repair genes are associated with Lynch syndrome who have elevated risk for colorectal cancer, prostate cancer, pancreatic cancer, urinary tract cancer, and specific skin cancers, as well as ovarian and uterine cancers in women.

Men with BRCA1 or 2  mutations should have screening started at age 40 years.

Germline genetic testing allows for a greater possibility for precision medicine indications.

Germline genetic testing in prostate cancer helps determine a patient’s hereditary cancer syndrome likelihood and guides family screening.

Sequencing DNA for acquire genetic changes (somatic mutations) requires prostate tumor material, cancer containing biopsies surgical material or circulating tumor cells or circulating tumor DNA in the blood.

Somatic mutations may change overtime due to genetic instability and selective pressure from therapy.

The identification of a germline mutation indicates a 50/50 chance that a first-degree relative inherited the same risk gene, and  recommendation is to share this information with relatives.

For germline BRCA2 mutation carries the relative risk of developing prostate cancer by age 65 years is estimated to be 2.5 to 8.6 fold compared with non-carriers.

Men with BRCA2 mutations present at a younger age with higher Gleason grade tumors, higher rates of nodal involvement, and distant metastases is at diagnosis, and higher of prostate cancer specific mortality.

BRCA2 and ATM are associated with aggressive and metastatic prostate cancer.

Germline mutations in the mismatch repair genes  MLH1, PMS2, MSH2 and MSH6  are associated with Lynch syndrome predisposing individuals to increase risk of cancers including colorectal, endometrial, and gastrointestinal.

There is a modest increase in prostate cancer in the Lynch syndrome.

Patients with microsattelite instability-high (MSI-high) or mismatch repair deficient (dMMR), or if there is a high tumor mutational burden generally defined as more than 10 mutations per megabase, it is more likely to respond to immunotherapy regimen such as Pembrolizumab than tumors without these characteristics.

The presence of mutations in or deletions of the tumor suppressor, genes, PTEN, RB1, or TP 53 does not generally affect treatment, since there are no specific drugs that restore the function of these genes.

Somatic tumor genomics testing can be used to safely choose active surveillance over definitive therapy such as surgery or radiation.

Somatic tumor genomics testing provides more information about risk than can be obtained from microscopic tumor analysis, and PSA testing alone.

Prostate cancer genetic testing is best in cases where the tumors are categorized as intermediate risk.

As many as one in seven patients with prostate cancer have a germline mutation and family members can be evaluated for testing.


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