PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

Preventive medicine has been dramatically improved by cancer genetics. The identification of susceptibility genes for hereditary forms of cancers in the past decades opened avenues for detection of second primary and recurrent tumors. Once a given germline mutation is detected, newly identified carriers are clinically investigated, and thus the diagnosis of tumors in an asymptomatic stage in the relatives of carriers becomes possible. Pheochromocytoma, paraganglioma, and associated inherited diseases served in this direction as important pacesetters. The susceptibility genes—including RET as causing multiple endocrine neoplasia type 2 (RefSeq NM_020975.4); VHL for von Hippel-Lindau disease (RefSeq NM_000551.3); SDHD, SDHC, and SDHB (succinate dehydrogenase subunits D [RefSeq NM_003002.3], C [RefSeq NM_003001.3], and B [RefSeq NM_003000.2]) for paraganglioma syndromes types 1, 3, and 4; and NF1 for neurofibromatosis type 1 (RefSeq NM_000267.3), herein summarized as classic susceptibility genes—have served as effective molecular tools for preventive medicine studies and practice in this field in the first years of the new millenium.^1-8 These studies led to the end of the 10% rule for the frequency of hereditary pheochromocytoma and instead pointed to at least a 24% hereditary fraction.^6,9 By 2010 and 2011, additional susceptibility genes for pheochromocytomas and paragangliomas were reported, including SDHA (succinate dehydrogenase subunit A [RefSeq NM_004168.3]), TMEM127 (transmembrane protein 127 [RefSeq NM_017849.3]), MAX (Myc-associated factor X [RefSeq NM_002382.4]), and SDHAF2 (succinate dehydrogenase complex assembly factor 2 [RefSeq NM_017841.2]).^10-13 In contrast to the classic susceptibility genes, recommendations of the last International Symposium for Pheochromocytoma (2014) do not provide clinical management guidelines for those with mutations in the susceptibility genes analyzed and characterized herein.¹⁴ The main reasons are the limited number of sufficiently large registries, leading to limited clinical data associated with mutations of these genes. The much-needed and important process of returning to the clinical roots is a labor-intensive one. Thus, our comprehensive genetic and clinical characterization study intends to close the gap between finding a mutation in 1 of these 4 new susceptibility genes and the associated clinical data so that gene-informed risk assessment, counseling, and management can be performed.

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the “PTEN-opathies.” Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.