Abstract SY04-03: Three components of inherited cancer risk and their implications in personalized cancer screening

Abstract

Abstract Inherited risk for cancer has been well established from twin studies and family studies. For example, a large, population-based study in Scandinavian countries of more than 200,000 same-sex twin pairs found that heritability was 33% for overall cancer and 57% for prostate cancer (1). At present, family history is the most commonly used method for evaluating an individual’s inherited risk for cancer. For those individuals with a strong family history, typically defined as multiple affected relatives or relatives who died of cancer at an early age, genetic testing of specific genes may also be recommended. However, recent data suggest that this standard of care is insufficient and inadequate for identifying individuals with higher inherited risk. Several recent studies suggest that inherited mutations in a number of high-penetrance genes (HPGs) are more common in cancer patients than previously estimated. In one study based on The Cancer Genome Atlas (TCGA) data, 4-19% of cancer patients harbored an HPG mutation, with 8% of prostate cancer patients found to be HPG mutation carriers (2). Furthermore, many mutation carriers do not have a positive family history. In our recent study of patients with prostate cancer, 60% of pathogenic mutation carriers of BRCA1/2 and ATM had a negative family history of prostate cancer (3).Therefore, it is necessary and relevant to include HPGs in cancer risk assessment among all subjects, regardless of family history. Another major component of inherited risk is cancer risk–associated SNPs. Many cancer risk–associated SNPs have been identified through genome-wide association studies. The validity of these SNPs has been well established, as they are statistically significant (P<5E-08) and have been replicated among independent study populations. Although each SNP has a small individual effect on cancer risk, they have a strong cumulative effect. The cumulative effect of these SNPs can be measured using several methods, including genetic risk score (GRS) (4). Because GRS is based on individuals’ genotypes and is a continuous variable, it is objective and informative in stratifying inherited risk of developing specific cancers. More importantly, GRS can identify considerably more high-risk subjects in the general population than family history. For example, in the Prostate Cancer Prevention Trial (PCPT), 24% of men in the study population had a GRS >1.4 and the prostate cancer detection rate during the 7 years of the study in these men was 33% (5). In contrast, 17% of men in the cohort had a positive family history and the prostate cancer detection rate in these men was 29%. Taken together, the latest data suggest that a comprehensive assessment of inherited cancer risk should include family history, HPGs, and GRS. These measures are complementary and, used together, can better identify subjects in the general population at elevated inherited risk for cancer. Using prostate cancer as an example, approximately 7-17% of men in the U.S. population have a positive family history of the disease and are therefore considered to have elevated inherited risk for prostate cancer (6,7). In addition, approximately 2% of men in the general population have a considerably higher inherited risk for prostate cancer due to harboring at least one pathogenic mutation in an HPG for prostate cancer (8). Many of these men do not have a positive family history. Finally, approximately 24% of men in the general population have higher GRSs (>1.4) and have an estimated prostate cancer risk equivalent to or even higher than a positive family history (5). Considering all three risk factors, approximately 36% of men in the general population are estimated to be at higher inherited risk for prostate cancer using this comprehensive risk assessment strategy, more than twice that of the current standard of care risk assessment. The more comprehensive assessment of inherited cancer risk has important clinical implications, both for asymptomatic subjects in the general population as well as for cancer patients. The most notable clinical utility is for developing individualized cancer screening strategies. A personalized cancer screening approach can maximize benefits and minimize harms associated with cancer screening. For example, offering PSA screening among men with higher inherited risk based on family history, HPGs, and GRS is a rational approach to address the current debate on prostate cancer screening. It is important to note that individualizing cancer screening is the most impactful component of precision medicine, as it can effectively reduce cancer-related mortality and improve quality of life.