Prostate Cancer Panel

Prostate cancer is the most frequently diagnosed cancer in males in the United States (Siegel et al. 2017. PubMed ID: 28055103). A man’s lifetime risk of developing invasive prostate cancer is 1 in 8 (Siegel et al. 2017. PubMed ID: 28055103). This disorder is typically considered a cancer of the elderly, and the median age of onset is ~68 years. However, recent studies suggest an increase in the incidence of early onset of prostate cancer (Gupta et al. 2017. PubMed ID: 28413383). Initially prostate cancer may be asymptomatic, but more advanced prostate cancers usually cause symptoms, which include problems urinating, blood in the urine, trouble getting an erection, and pain in the hips, spine and chest (American Cancer Society. 2014). When prostate cancer is limited to the prostate gland itself, it may be curable. However, cancer cells may spread to other parts of the body, particularly the lymph nodes and bones (American Cancer Society. 2014). Early diagnosis is critical to successful treatment.

Prostate cancer is highly heritable, with an overall estimated heritability of 40% - 60% (Lichtenstein et al. 2000. PubMed ID: 10891514; Hjelmborg et al. 2014. PubMed ID: 24812039). Approximately 5% -10% of prostate cancer is caused by rare pathogenic variants in susceptibility genes (Steinberg et al. 1990. PubMed ID: 2251225; Carter et al. 1992. PubMed ID: 1565627; Pritchard et al. 2016. PubMed ID: 27433846). The mode of inheritance appears to be autosomal dominant (AD) (Schaid et al. 1998. PubMed ID: 9585590).

This prostate cancer next generation sequencing panel assesses genes that have been shown to be causative when mutated for disorders that have prostate cancer as a clinical feature.

ATM: Ataxia-telangiectasia is an autosomal recessive disorder caused by pathogenic variants in the ATM gene. ATM encodes a serine protein kinase (ATM) that is involved in DNA repair via phosphorylation of downstream proteins. It senses double-strand DNA breaks, coordinates cell-cycle checkpoints prior to repair, and recruits repair proteins to damaged DNA sites (Taylor et al. 2004. PubMed ID: 15279810). Pathogenic variants in ATM result in defective checkpoint cycling. Previous studies suggest an association between ATM heterozygous carriers and prostate cancer susceptibility. For example, a retrospective case series of patients with prostate cancer found that 1.6% (11 of 692) had an ATM pathogenic variant (Pritchard et al. 2016. PubMed ID: 27433846). Specific variants, such as ATM p.Ser49Cys, have been found to be associated with an increased risk of prostate cancer (Dombernowsky et al. 2008. PubMed ID: 18565893).

BRCA1 and BRCA2: BRCA1 is a tumor suppressor gene that is involved in a number of cellular processes including DNA damage repair, cell cycle progression, gene transcription and ubiquitination. BRCA2 is a tumor suppressor gene that along with RAD51 has a large role in DNA repair processes and genome stability. Male carriers of BRCA1 and BRCA2 pathogenic variants have a higher risk of developing cancers, including prostate cancer (Thompson and Easton. 2002. PubMed ID: 12237281; Liede et al. 2004. PubMed ID: 14966099). Particularly, prostate cancer has been observed at higher rates in BRCA2 carriers than in the general population (Mersch et al. 2015. PubMed ID: 25224030).

CHEK2: CHEK2 encodes a protein kinase that protects the genome from ionizing radiation and genotoxic insults. To date, approximately 90 pathogenic variants have been reported throughout the CHEK2 gene, and >90% are detectable by sequencing (Human Gene Mutation Database). It has been suggested that CHEK2 may be a potential prostate cancer susceptibility gene (Wang et al. 2015. PubMed ID: 26629066).

HOXB13: HOXB13 is involved in embryonic development and regulation of androgen receptor target genes. It is a tumor suppressor, and germline variants have been associated with prostate cancer susceptibility with an odds ratio of 3-8 (Zhen et al. 2018. PubMed ID: 29669169).

MLH1, MSH2, MSH6, PMS2, and EPCAM: Germline pathogenic variants in these genes have been associated with Lynch syndrome. Previous studies have suggested that prostate cancer may be observed in patients harboring a mismatch repair (MMR) gene pathogenic variant (Grindedal et al. 2009. PubMed ID: 19723918; Haraldsdottir et al. 2014. PubMed ID: 24434690: Rosty et al. 2014. PubMed ID: 25117503).

NBN: Nijmegen breakage syndrome (NBS) has been associated with an elevated risk of prostate cancer (Cybulski et al. 2013. PubMed ID: 23149842; Cybulski et al. 2004. PubMed ID: 14973119). The NBN protein normally associates with the MRE11A and RAD50 proteins to form the MRN complex. The MRN complex, upon DNA damage, is involved in DNA repair and cell cycle arrest via the ATM kinase. Pathogenic variants in NBN lead to faulty DNA repair and improper cell cycle control. In Eastern European with NBS, c.657_661del5 is the most common pathogenic variant and accounts for more than 90% of all mutant alleles in NBN (Varon et al. 1998. PubMed ID: 9590180).

TP53: Li-Fraumeni syndrome (LFS) is inherited in an autosomal dominant manner and is caused by heterozygous germline pathogenic variants in the TP53 gene (Malkin et al. 1990. PubMed ID: 1978757; Srivastava et al. 1990. PubMed ID: 2259385). TP53 encodes the often studied cellular tumor p53 antigen (Soussi. 2010. PubMed ID: 20930848). p53 is a ubiquitously expressed DNA-binding protein that plays a major role in the regulation of cell division, DNA repair, programmed cell death, and metabolism. More than 200 pathogenic variants have been reported throughout the TP53 gene, and nearly all are detectable by DNA sequencing (Human Gene Mutation Database). Several gross deletions encompassing one or more exons of the TP53 gene have been described (Human Gene Mutation Database), but these account for less than 1% of all LFS patients (Schneider et al. 2013. PubMed ID: 20301488). The average risk of developing cancer for carriers of TP53 pathogenic variants has been estimated to be ~73% for men (Chompret et al. 2000. PubMed ID: 10864200). In a Dutch case series of 180 families with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome, a TP53 pathogenic variant was identified in 24 families (Ruijs et al. 2010. PubMed ID: 20522432). Li-Fraumeni syndrome is responsible for multiple cancers including prostate cancer. In a French case series of 214 families with TP53 pathogenic variants, 4 prostate cancer cases were reported (Bougeard et al. 2015. PubMed ID: 26014290).

A few other genes such as PALB2, RAD51C and RAD51D are included in this NGS panel based on preliminary evidence of their involvement in prostate cancer (Pritchard et al. 2016. PubMed ID: 27433846).

This panel analyzes genes that have been associated with hereditary prostate cancer. It is difficult to estimate the clinical sensitivity of this test due to the paucity of large cohort studies. However, in a recent study of 692 men with documented metastatic prostate cancer, pathogenic variants in these genes were identified: ATM (11 pathogenic variants [1.6%l]), BRCA1 (6 [0.9%]), BRCA2 (37 [5.3%]), CHEK2 (10 [1.9%]), and PALB2 (3 [0.4%]) (Pritchard et al. 2016. PubMed ID: 27433846).

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

This test also includes analysis of the inversion of exons 1-7 in MSH2.

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is not typically included in this test but can be ordered separately using test code 6062, if desired.