Multigene testing of moderate-risk genes: be mindful of the missense.

BACKGROUND: Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established. METHODS: We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold. RESULTS: Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5. CONCLUSIONS: Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

PTEN mosaicism with features of Cowden syndrome.

We present the first known case of somatic PTEN mosaicism causing features of Cowden syndrome (CS) and inheritance in the subsequent generation. A 20-year-old woman presented for genetics evaluation with multiple ganglioneuromas of the colon. On examination, she was found to have a thyroid goiter, macrocephaly, and tongue papules, all suggestive of CS. However, her reported family history was not suspicious for CS. A deleterious PTEN mutation was identified in blood lymphocytes, 966A>G, 967delA. Genetic testing was recommended for her parents. Her 48-year-old father was referred for evaluation and was found to have macrocephaly and a history of Hashimoto's thyroiditis, but no other features of CS. Site-specific genetic testing carried out on blood lymphocytes showed mosaicism for the same PTEN mutation identified in his daughter. Identifying PTEN mosaicism in the proband's father had significant implications for the risk assessment/genetic testing plan for the rest of his family. His result also provides impetus for somatic mosaicism in a parent to be considered when a de novo PTEN mutation is suspected.

Photobinding of 3H 8-methoxypsoralen to monkey intraocular tissues.

Young (less than 1 year) and old (greater than 15 years) Rhesus monkeys were utilized in this study in order to determine whether ultraviolet (UV) radiation at ambient levels induces psoralen photobinding in primate eyes (in particular the lens and retina). Unilateral aphakia or pseudophakia was induced surgically and the eyes were allowed to heal. The animals then were given a single intraperitoneal injection of 3H 8-methoxypsoralen (8-MOP) and immediately exposed to BLB lights (of measured radiation intensity at the corneal surface). The animals were killed at varying time periods (2-6 weeks), and the eyes were removed immediately. One-half of each cornea and lens was frozen for subsequent optical spectroscopy and the remaining ocular tissues were fixed for histopathologic studies and autoradiography. These data demonstrate that low level UV radiation (less than 0.4 mW/cm2) can cause 8-MOP photobinding to lens proteins and DNA and to aphakic, pseudophakic, and young phakic primate retinas. The older phakic primate lens serves as a protective UV filter and prevents psoralen photobinding within the retina. These data suggest that older aphakes and pseudophakes may require UV radiation protection to prevent direct as well as photosensitized retinal photodamage.

Interest and informational preferences regarding genomic testing for modest increases in colorectal cancer risk.

BACKGROUND/AIMS: This study explored the interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer. METHODS: Surveys were conducted on 272 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhal's Common Sense Model of Self-Regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with interest in SNP testing and preferences for receiving genomic risk communications. RESULTS: Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials (69.5%), oncologists (54.8%), primary-care physicians (58.4%), and the web (58.1%). Overall, persons who were unmarried (p = 0.029), younger (p = 0.003) and with greater cancer-related fear (p = 0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer-related fear was associated with the interest in predictive genomic testing in the intervention group (p = 0.017), but not the control group. CONCLUSIONS: Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups and those with greater cancer fear.

Antibiotics, the pill, and pregnancy.

OBJECTIVES: To establish if advice concerning risks of pregnancy when taking oral contraceptive pill and antibiotics is being offered. METHOD: A retrospective audit of notes of 100 female patients aged 15-39 who were prescribed antibiotics. RESULTS: Documentation of use of contraception was noted in 3% of patients. Advice concerning risks and further precautions was noted in this 3% but not in any other records. CONCLUSION: The audit identified a gap in documentation and/or clinical practice in advising women of childbearing age of the risk of conceiving when using oral contraceptive pill and antibiotics. Recommendations are given as to how this may be addressed.

Impaired intestinal absorption of dipeptide in tropical sprue patients in India.

1. Intestinal absorption of glycylglycine was studied in four control subjects and six patients with tropical sprue by using a direct technique of intestinal perfusion. 2. The patients with tropical sprue showed significant impairment in the absorption of the dipeptide.

Intestinal absorption in normal Indian and English people.

The absorption of glycine, glycylglycine, water, and electrolytes was studied by intestinal perfusion in normal Indian and English people. Compared with the English people the Indians showed impaired absorption of all four substances. In the Indians the absorption of glycine and glycylglycine was impaired to the same extent, so that the kinetic advantage of glycylglycine as compared with glycine was preserved. The reduced absorption in the Indians may be the functional counterpart of the minor morphological changes seen in the jejunal mucosa of people living in southern India.