Heritability of prostate cancer: a tale of rare variants and common single nucleotide polymorphisms

Abstract

Prostate cancer (PCa) is the most common non-skin cancer men in developed countries. Despite years of research, no strong modifiable risk factor for PCa has been found. The two most significant cancer risk factors, smoking and obesity, do not appear to be strong risk factors for PCa. A recent systematic review and meta-analysis summarized the current literature of tobacco use and PCa mortality and incidence (1). This meta-analysis included 51 cohort studies (50,349 incident cases and 4,082,606 cohort participants) and found a dichotomized association between smoking and PCa risk. Current smoking was associated with an increased risk of PCa [rate ratio (RR): 1.06; 95% confidence interval (CI), 0.98-1.15] in studies completed in 1995 or earlier [before the prostate-specific antigen (PSA) screening era], and a reduced risk of PCa (RR: 0.84, 95% CI, 0.79-0.89) in studies completed afterward (after the wide spread of PSA screening). These data suggest that smoking may reduce the risk of indolent non-aggressive cancers that have predominated in more recent years, while promoting more aggressive cancers. Likewise, there also appears to be a dual effect of obesity on PCa incidence. A metaanalysis of multiple prospective studies found that obesity had a slightly protective effect in localized PCa (RR: 0.94, 95% CI, 0.91-0.97), but was associated with an increased incidence of advanced PCa (RR: 1.09, 95% CI, 1.02-1.16) for every five units of body mass index (BMI) increase (2).Age is the most important risk factor for PCa: the lifetime The lifetime probability of being diagnosed with PCa was 0.3 (1 in 325) for those aged younger than 50 years, 2.1 (1 in 48) for 50-59 year old men, 5.8 (1 in 17) for 60-69 year old men, and10.0 (1 in 10) for those aged 70 years and above (3). Another major risk factor for PCa is race: the incidence rate among African Americans is about 70% higher than that among whites (4). In addition, genetic susceptibility plays an important role in PCa etiology. Earlier studies on familial aggregation of cancer clearly showed familial clustering of PCa. A meta-analysis of 33 independent studies demonstrates a pooled RR of 2.48 (95% CI, 2.25-2.74) for men with a first-degree family history (i.e., affected father or brother) and the RR increases to 4.39 (95% CI, 2.61-7.39) for those with two or more affected first-degree family members (5). The large classic Nordic Twin study recently estimated a heritability of about 58% for PCa, much higher than all the other common nonskin cancers (e.g., lung cancer, 18%; breast cancer, 31%; and colon cancer, 15%), whereas shared environment has negligible effect (0%) on PCa development, compared to 24%, 16%, and 16% for lung, breast, and colon cancer, respectively (6,7).Given the high heritability of PCa, there have been enormous efforts on identifying inherited genetic susceptibility loci for PCa. Many genome-wide association studies (GWAS) have been performed across different ethnicities and over 100 common, low-penetrance PCa predisposing variants have currently be...

Genomic Prediction of Complex Disease Risk

“…18. It has long been known that age is a significant risk factor for prostate cancer, but GWAS studies have shown that there is a significant genetic component [64]. Additionally, it has been shown, using genome wide complex trait analysis (GCTA), that variants with minor allele frequency 0.1 − 1% make up an important contribution to "missing heritablity" for men of African ancestry [65].…”

Age-related late-onset disease heritability patterns and implications for genome-wide association studies

“…As with breast cancer, the fraction of PC attributed to highly malignant mutations is low. Known rare, higheffect-size variants such as BRCA1/2, ATM, and HOXB13 explain only 10-12% of heritability (Wu and Gu, 2016;Mancuso et al, 2016;Walsh, 2017;Lecarpentier et al, 2017). Recently, Eeles et al (2017) using an imputed meta-analysis for 145,000 men, reported that the GWAS polygenic score they obtained explains 33% of the familial relative risk.…”

“…Recently, Eeles et al (2017) using an imputed meta-analysis for 145,000 men, reported that the GWAS polygenic score they obtained explains 33% of the familial relative risk. Wu and Gu (2016) concluded that the search for the missing heritability may be better served by high-coverage whole-genome sequencing (WGS); however, due to the cost and complexity, it is not currently feasible to obtain this much high-quality data. In the absence of more predictive genetic data, Wu and Gu (2016) noted that the best predictor of PC is age itself.…”

“…Wu and Gu (2016) concluded that the search for the missing heritability may be better served by high-coverage whole-genome sequencing (WGS); however, due to the cost and complexity, it is not currently feasible to obtain this much high-quality data. In the absence of more predictive genetic data, Wu and Gu (2016) noted that the best predictor of PC is age itself. Prostate cancer conclusions: The conclusions for PC heritability are very much the same as for breast cancer.…”

“…The mostly polygenic fraction of lung cancer heritability is hypothesized to be similarly stable with age, as is the case with the other three cancers reviewed. (Ford et al, 1998;Antoniou et al, 2003;Risch et al, 2006;Mavaddat et al, 2010;Haley, 2016;Michailidou et al, 2017) (Hjelmborg et al, 2014;Wu and Gu, 2016;Mancuso et al, 2016;Walsh, 2017;Lecarpentier et al, 2017;Eeles et al, 2017) (Jiao et al, 2014;Schmit et al, 2016;de Voer et al, 2016;) (Krewski et al, 2005;Weissfeld et al, 2015;Carr et al, 2015;Malhotra et al, 2016;Kanwal et al, 2017;Shi et al, 2017; Lifetime risk numbers, when marked, "w" for women, "m" for men. Lifetime risk numbers, when marked, "w" for women, "m" for men.…”