Prostate Carcinoma: Hereditary and Predictive Aspects of Molecular Pathology

Prostate cancer is the second most common cancer in men and the most common cause of cancer-related deaths. Every year, there are 1.6 million new cases and 366,000 deaths worldwide. The lifetime risk of a man developing prostate cancer is approximately 13 %. Known risk factors are age, ethnic origin and a positive family history. Prostate carcinoma has the greatest hereditary potential in men compared to all other types of cancer: we know of around 170 gene loci that are distributed across almost all chromosomes and are associated with the development of prostate carcinoma – usually cumulatively. However, 10 % of all prostate cancers are inherited monogenically, autosomal dominant.

Hereditary prostate carcinoma is suspected if a patient is diagnosed at a young age, if the tumour is already at an advanced stage when it is first diagnosed and if the tumour takes an aggressive course. The risk of recurrence after tumour resection is increased. Interestingly, however, there are no major differences in overall survival compared to sporadic prostate carcinomas. Hereditary prostate carcinomas have an association with hereditary tumour syndromes such as hereditary breast and ovarian carcinomas (HBOC) and Lynch syndrome. Therefore, a family history should also include questions about cancer in the patient’s female relatives.

79 to 92 % of the genetic changes that lead to the development of prostate cancer are still unknown. The ones that we do know – like most genes that favour the development of other types of cancer – are associated with DNA repair.

BRCA 1/2

The best known of these genes are BRCA (BReast CAncer gene) 1 and 2: these are tumour suppressor genes on chromosomes 17 and 13, which are responsible for repairing DNA double-strand breaks through homologous recombination. A defect in these genes leads to homologous recombination deficiency (HRD). In a patient with a germ-line mutation, the risk of pancreatic cancer increases 3.8-fold for BRCA 1 and 8.6-fold for BRCA 2. BRCA 1/2 is also the high-risk gene for breast and ovarian cancer. The mutation is relatively frequent in the general population (1:400).

BRCA 2 mutations are often found in metastasised and/or castration-resistant carcinomas. They lead to poorer survival compared to BRCA 1 mutations and to sporadic prostate carcinoma.

ATM

The ATM (Ataxia Teleangiectasia Mutated) gene is a signal transducer for DNA damage localised on chromosome 11. It regulates the cellular response to DNA damage by activating cell cycle proteins and DNA repair proteins. In the case of a mutation, the relative risk of metastasising prostate carcinoma is 6.3 % and the risk of breast, colon, stomach and pancreatic carcinomas is also increased.

MMR

MMR (MisMatch Repair) genes are associated with Lynch syndrome. Mutations have a low prevalence, but lead to an increased risk of prostate carcinoma when they occur. A mutation of the MSH2 (MutS homologue 2) gene increases the risk by up to 24 %. Carcinomas caused by MMR mutations do not occur at a young age and generally do not have an aggressive phenotype (with the exception of MSH2). Mutation carriers primarily have an increased risk of colon and endometrial carcinomas, but also of various other carcinomas such as urothelium, stomach, small intestine and pancreas carcinomas. 

HOXB13

HOXB13 (HomeobOX B13) is the most frequently mutated gene in hereditary prostate cancer – with a mutation rate of 1:400 in the general population. It codes for an essential transcription factor for the embryonic development of the prostate. The penetrance – i. e. the percentage probability with which a certain genotype leads to the development of the associated phenotype – is very high here at 40 to 60 % up to the age of 80. If there is a positive family history of early prostate carcinoma, it is almost 100 %. The HOXB13 mutation has no specific association with high-risk carcinomas and is also not a risk factor for other organ system tumours – not even for female carriers [1, 2].

Polygenic Risk Score

The Polygenic Risk Score (PRS) can theoretically be used to calculate the personal risk of prostate cancer for each patient. The statistical method measures the cumulative effect of multiple known low-risk Single Nucleotide Polymorphisms (SNPs). The method becomes more meaningful the more SNPs are included. The PRS is measured in percentiles and, together with the family history and any gene mutations, can indicate the individual cancer risk (Fig. 1). 

There is a strong association between a high PRS, an increased risk of prostate cancer and an early age of onset [3].

Genetic Testing

Genetic testing is recommended for all patients with metastasised prostate carcinoma or high-risk carcinoma. In addition, if there is a positive family history, i. e. if a brother, father or at least two relatives under the age of 60 developed prostate cancer, genetic testing is advisable. And also if more than one family member has been diagnosed with breast, ovarian or pancreatic cancer (suggestive of BRCA 2 mutation) or Lynch syndrome or Lynch syndrome-associated tumours [1].

Specific genetic alterations occur at each stage of prostate carcinoma; they are shown in Fig. 2. 

Various gene fusions, mutations, insertions and deletions as well as the above-mentioned germline mutations occur in the primary stage. In metastasised carcinomas, further alterations can occur – very frequently of P53 or BRCA 1/2. In castration-resistant prostate carcinomas, the genetic alterations are associated with the androgen receptor.

Personalised Therapy

Of the numerous mutations that occur in prostate cancer, not all are actionable targets for a personalised therapy approach. The ESCAT score (ESMO Scale of Clinical Actionability for molecular Targets) quantifies which gene alterations can be specifically treated [6]. 57 % of prostate carcinomas have genetic alterations that are potentially treatable with drugs (min. evidence tier II).

4 % of prostate carcinomas have a high mutation rate with 20 or more mutations per megabase or high microsatellite instability, which predestine them for treatment with immune checkpoint inhibitors.

Homologous recombination in prostate cancer is most frequently caused by BRCA 2 mutations (just under 10 %) and ATM mutations (over 5 %). These are mostly somatic (i. e. only present in the tumour and not in the germline):

• 75 % of BRCA 1 mutations
• 42 % of BRCA 2 mutations
• 64 % of ATM mutations
• 48 % of FANCA (Fanconi anemia complementation group A) mutations

gLOH (genome-wide loss of heterozygosity) is significantly increased in prostate carcinomas with BRCA 1/2 and ATR mutations. gLOH is a biomarker for HRD and potentially also for sensitivity to PARP (poly[ADP-ribose] polymerase) inhibitors [5, 7]. 

In the TRITON II study, patients with metastatic castration-resistant prostate cancer with BRCA 1/2 alteration were treated with rRucaparib. On imaging, the tumour mass decreased in 47.5 % of patients and the PSA (prostate-specific antigen) value decreased in 53.6 % of patients [8]. 

In the PROfound study Olaparib improved median PFS (progression-free survival) in Cohort A (7.4 months vs 3.6 months with physician’s choice medication/standard therapy). In analysis of Cohorts A+B, PFS improvement was reduced, but remained significant (5.8 months vs 3.5 months) [9]. 

Therefore, sequencing of genes associated with high recombination is also recommended with a high level of evidence in the German S3 guideline on prostate cancer from May 2024 before systemic therapy [10]. 

Genetic analysis provides insights into existing alterations and guides treatment recommendations accordingly (Fig. 3).