Comprehensive Breast Cancer Risk Assessment for CHEK2 and ATM Pathogenic Variant Carriers Incorporating a Polygenic Risk Score and the Tyrer-Cuzick Model.

PURPOSE: Breast cancer risks for CHEK2 and ATM pathogenic variant (PV) carriers are modified by an 86-single nucleotide polymorphism polygenic risk score (PRS) and individual clinical factors. Here, we describe comprehensive risk prediction models for women of European ancestry combining PV status, PRS, and individual clinical variables. MATERIALS AND METHODS: This study included deidentified clinical records from 358,095 women of European ancestry who received testing with a multigene panel (September 2013 to November 2019). Model development included CHEK2 PV carriers (n = 4,286), ATM PV carriers (n = 2,666), and women negative for other breast cancer risk gene PVs (n = 351,143). Odds ratios (ORs) were calculated using multivariable logistic regression with adjustment for familial cancer history. Risk estimates incorporating PV status, PRS, and Tyrer-Cuzick v7.02 were calculated using a Fixed-Stratified method that accounts for correlations between risk factors. Stratification of PV carriers into risk categories on the basis of remaining lifetime risk (RLR) was assessed in independent cohorts of PV carriers. RESULTS: ORs for association of PV status with breast cancer were 2.01 (95% CI, 1.88 to 2.16) and 1.83 (95% CI, 1.68 to 2.00) for CHEK2 and ATM PV carriers, respectively. ORs for PRS per one standard deviation were 1.51 (95% CI, 1.37 to 1.66) and 1.45 (95% CI, 1.30 to 1.64) in CHEK2 and ATM PV carriers, respectively. Using the combined model (PRS plus Tyrer-Cuzick plus PV status), RLR was low (≤ 20%) for 24.2% of CHEK2 PV carriers, medium (20%-50%) for 63.8%, and high (> 50%) for 12.0%. Among ATM PV carriers, RLR was low for 31.5% of patients, medium for 58.5%, and high for 9.7%. CONCLUSION: In CHEK2 and ATM PV carriers, risk assessment including PRS, Tyrer-Cuzick, and PV status has the potential for more precise direction of screening and prevention strategies.

Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases.

Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice.

Circumcision rates in the United States: rising or falling? What effect might the new affirmative pediatric policy statement have?

The objective of this review was to assess the trend in the US male circumcision rate and the impact that the affirmative 2012 American Academy of Pediatrics policy statement might have on neonatal circumcision practice. We searched PubMed for the term circumcision to retrieve relevant articles. This review was prompted by a recent report by the Centers for Disease Control and Prevention that found a slight increase, from 79% to 81%, in the prevalence of circumcision in males aged 14 to 59 years during the past decade. There were racial and ethnic disparities, with prevalence rising to 91% in white, 76% in black, and 44% in Hispanic males. Because data on neonatal circumcision are equivocal, we undertook a critical analysis of hospital discharge data. After correction for underreporting, we found that the percentage had declined from 83% in the 1960s to 77% by 2010. A risk-benefit analysis of conditions that neonatal circumcision protects against revealed that benefits exceed risks by at least 100 to 1 and that over their lifetime, half of uncircumcised males will require treatment for a medical condition associated with retention of the foreskin. Other analyses show that neonatal male circumcision is cost-effective for disease prevention. The benefits of circumcision begin in the neonatal period by protection against infections that can damage the pediatric kidney. Given the substantial risk of adverse conditions and disease, some argue that failure to circumcise a baby boy may be unethical because it diminishes his right to good health. There is no long-term adverse effect of neonatal circumcision on sexual function or pleasure. The affirmative 2012 American Academy of Pediatrics policy supports parental education about, access to, and insurance and Medicaid coverage for elective infant circumcision. As with vaccination, circumcision of newborn boys should be part of public health policies. Campaigns should prioritize population subgroups with lower circumcision prevalence and a higher burden of diseases that can be ameliorated by circumcision.

Recommendation by a law body to ban infant male circumcision has serious worldwide implications for pediatric practice and human rights.

BACKGROUND: Recent attempts in the USA and Europe to ban the circumcision of male children have been unsuccessful. Of current concern is a report by the Tasmanian Law Reform Institute (TLRI) recommending that non-therapeutic circumcision be prohibited, with parents and doctors risking criminal sanctions except where the parents have strong religious and ethnic ties to circumcision. The acceptance of this recommendation would create a precedent for legislation elsewhere in the world, thereby posing a threat to pediatric practice, parental responsibilities and freedoms, and public health. DISCUSSION: The TLRI report ignores the scientific consensus within medical literature about circumcision. It contains legal and ethical arguments that are seriously flawed. Dispassionate ethical arguments and the United Nations Convention on the Rights of the Child are consistent with parents being permitted to authorize circumcision for their male child. Uncritical acceptance of the TLRI report's recommendations would strengthen and legitimize efforts to ban childhood male circumcision not just in Australia, but in other countries as well. The medical profession should be concerned about any attempt to criminalize a well-accepted and evidence-based medical procedure. The recommendations are illogical, pose potential dangers and seem unworkable in practice. There is no explanation of how the State could impose criminal charges against doctors and parents, nor of how such a punitive apparatus could be structured, nor how strength of ethnic or religious ties could be determined. The proposal could easily be used inappropriately, and discriminates against parents not tied to the religions specified. With time, religious exemptions could subsequently be overturned. The law, governments and the medical profession should reject the TLRI recommendations, especially since the recent affirmative infant male circumcision policy statement by the American Academy of Pediatrics attests to the significant individual and public health benefits and low risk of infant male circumcision. SUMMARY: Doctors should be allowed to perform medical procedures based on sound evidence of effectiveness and safety with guaranteed protection. Parents should be free to act in the best interests of the health of their infant son by having him circumcised should they choose.

Should male circumcision be advocated for genital cancer prevention?

The recent policy statement by the Cancer Council of Australia on infant circumcision and cancer prevention and the announcement that the quadrivalent human papillomavirus (HPV) vaccine will be made available for boys in Australia prompted us to provide an assessment of genital cancer prevention. While HPV vaccination of boys should help reduce anal cancer in homosexual men and cervical cancer in women, it will have little or no impact on penile or prostate cancer. Male circumcision can reduce cervical, penile and possibly prostate cancer. Promotion of both HPV vaccination and male circumcision will synergistically maximize genital cancer prevention.

A 'snip' in time: what is the best age to circumcise?

BACKGROUND: Circumcision is a common procedure, but regional and societal attitudes differ on whether there is a need for a male to be circumcised and, if so, at what age. This is an important issue for many parents, but also pediatricians, other doctors, policy makers, public health authorities, medical bodies, and males themselves. DISCUSSION: We show here that infancy is an optimal time for clinical circumcision because an infant's low mobility facilitates the use of local anesthesia, sutures are not required, healing is quick, cosmetic outcome is usually excellent, costs are minimal, and complications are uncommon. The benefits of infant circumcision include prevention of urinary tract infections (a cause of renal scarring), reduction in risk of inflammatory foreskin conditions such as balanoposthitis, foreskin injuries, phimosis and paraphimosis. When the boy later becomes sexually active he has substantial protection against risk of HIV and other viral sexually transmitted infections such as genital herpes and oncogenic human papillomavirus, as well as penile cancer. The risk of cervical cancer in his female partner(s) is also reduced. Circumcision in adolescence or adulthood may evoke a fear of pain, penile damage or reduced sexual pleasure, even though unfounded. Time off work or school will be needed, cost is much greater, as are risks of complications, healing is slower, and stitches or tissue glue must be used. SUMMARY: Infant circumcision is safe, simple, convenient and cost-effective. The available evidence strongly supports infancy as the optimal time for circumcision.

Why circumcision is a biomedical imperative for the 21(st) century.

Circumcision of males represents a surgical "vaccine" against a wide variety of infections, adverse medical conditions and potentially fatal diseases over their lifetime, and also protects their sexual partners. In experienced hands, this common, inexpensive procedure is very safe, can be pain-free and can be performed at any age. The benefits vastly outweigh risks. The enormous public health benefits include protection from urinary tract infections, sexually transmitted HIV, HPV, syphilis and chancroid, penile and prostate cancer, phimosis, thrush, and inflammatory dermatoses. In women circumcision of the male partner provides substantial protection from cervical cancer and chlamydia. Circumcision has socio-sexual benefits and reduces sexual problems with age. It has no adverse effect on penile sensitivity, function, or sensation during sexual arousal. Most women prefer the circumcised penis for appearance, hygiene and sex. Given the convincing epidemiological evidence and biological support, routine circumcision should be highly recommended by all health professionals.

An assessment of CME needs of Canadian urologists.

The Canadian Urological Association has recently developed a new continuing medical education vehicle, Video Journal in Urology. The editorial content of this quarterly production is determined by the results of a needs assessment, the results of which are described in this paper. The needs assessment, as a two-page questionnaire, was mailed to 504 urologists. One hundred and eight-three responded, a response rate of 36.3%. The topic areas ranked as most interesting were largely centered around the broad topic of prostate cancer.