Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing.

BACKGROUND: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included. PATIENTS AND METHODS: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes. RESULTS: Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. CONCLUSIONS: These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.

Plasma beta-endorphin levels in silent myocardial ischemia induced by exercise.

Although silent myocardial ischemia is a well recognized phenomenon, the reasons for the lack of symptoms in patients with coronary artery disease (CAD) is unclear. Because the endogenous opioid beta-endorphin has been related to pain modulation, plasma beta-endorphin levels were studied before, during and after exercise-induced ischemia in symptomatic and asymptomatic men. Because beta-endorphin responses have been closely linked to adrenocorticotropic hormone (ACTH) and cortisol responses, these hormones also were measured. Nine symptomatic and 12 asymptomatic patients with a high probability (at least 95%) of CAD and 8 apparently healthy men completed a Bruce protocol treadmill test. Blood samples were drawn before, during and 10 minutes after exercise. During exercise the measured hormones showed no significant increases from basal levels. However, plasma beta-endorphin, ACTH and cortisol levels were significantly elevated (p less than or equal to 0.01) 10 minutes after exercise in all 3 groups. There was no significant difference in plasma beta-endorphin levels during or after exercise between the symptomatic and asymptomatic patients with CAD. Thus, differences in circulating levels of beta-endorphin, ACTH and cortisol are not associated with the presence or absence of pain during exercise-induced myocardial ischemia.

Role of solute in the early restitution of blood volume after hemorrhage.

We examined the putative roles of decreased capillary pressure and increased transcapillary osmolar gradient in mediation of the early restitution of blood volume after hemorrhage by comparing the degree of restitution of plasma volume and protein and comparing changes in capillary pressure and osmolality in awake dogs with those in dogs anesthetized with pentobarbital. Decreases in estimated capillary pressure and increases in plasma osmolality were greater in anesthetized than in awake dogs. However, early restitution of plasma volume and of protein was greater in awake animals. Analysis of the Starling forces indicated that interstitial hydrostatic pressure was greater in awake animals than in anesthetized animals, suggesting that interstitial volume increases more rapidly in awake animals. Selective venous sampling in anesthetized dogs indicated that the splanchnic and renal vascular beds release solute to the circulation following hemorrhage. However, rather than promoting the restitution of blood volume by production of a transcapillary osmolar gradient, the data suggest that the solute is delivered to the peripheral tissues, where it mediates the movement of water from cells to the interstitium more rapidly in awake than in anesthetized dogs. It thus appears that the early metabolic changes after hemorrhage, resulting in increased solute production, are important for the early restitution of blood volume and plasma protein.

Glucose and osmolality as predictors of injury severity.

Elevation in osmolality occurs after both injury and experimental hemorrhage. Similar elevations in glucose and cortisol have been found to correlate with both injury severity and survival. In this study, we have investigated the relationship between the severity of trauma and changes in glucose, osmolality, and cortisol in injured patients. Trauma severity was estimated using the Injury Severity Score, and correlation coefficients were computed for the three measured variables. Elevations in both osmolality and glucose correlated positively with severity of injury, whereas cortisol did not correlate. Although glucose and alcohol contributed to the rise in osmolality, they did not account for the entire increase. The results indicate that measured increases in osmolality and glucose following trauma may be useful in the prospective evaluation of its severity, especially in those patients with occult major injury. The lack of correlation of increased cortisol with injury severity suggests an interaction of multiple hormones resulting in the increase in osmolality and glucose.

Circadian rhythmicity of ACTH and corticosterone in the rat.

The circadian secretion of ACTH and corticosterone was assessed by measuring immunoreactive ACTH concentration in the plasma and ACTH content in the anterior and posterior pituitary over a 30 h period in groups of both male and female rats and comparing these data to fluorometric corticosterone concentration in the plasma and corticosterone content in the adrenal. A circadian rhythm of plasma corticosterone levels and adrenal content was apparent in both males and females with the highest levels at the onset of darkness. In contrast, there was no significant circadian rhythm in plasma ACTH levels or anterior or posterior ACTH pituitary content. Because the ACTH and corticosterone rhythms were dissociated, rhythmic corticosterone secretion is not entirely dependent on ACTH secretion.

Impaired restitution of blood volume after large hemorrhage.

Previous studies have suggested that increases in extracellular osmolality mediate a shift of intracellular fluid into the interstitium following 10% hemorrhage. This unidirectional fluid movement is required for full restitution of blood volume (BV) and for cardiovascular stabilization. The extent to which this mechanisms acts in larger hemorrhages was examined in these studies. Forty-two dogs were studies 3 weeks after splenectomy. Twenty were anesthetized with pentobarbital, the others were studied awake. Hemorrhages of 10% (7.5 ml/kg, 15 dogs), 20% (15 ml/kg, 13 dogs), and 30% (22.5 ml/kg, 15 dogs) were carried out over 3 minutes. Patterns of changes in osmolality, total plasma protein content, and blood volume were identical in the two groups, although osmolality was significantly greater during the first 2 hours in anesthetized dogs. Osmolality increased with increasing degrees of hemorrhage, providing an increasing driving force for fluid shifts. Restitution of BV was significantly greater after 20% hemorrhage than after 10% hemorrhage. However, restitution of BV after 30% hemorrhage was no greater than after 10% hemorrhage. Patterns of protein restitution paralleled changes in BV. Cunningham, Shires, and Wagner (7) reported fluid shifts into cells after a 30% hemorrhage associated with a fall in membrane potential. It thus appears likely that a fluid shift out of cells in response to increased osmolality is offset by shifts into cells as the magnitude of hemorrhage becomes large. This failure of homeostatic restoration of BV with consequent failure of cardiovascular stabilization may represent an early event in the development of hemorrhagic shock.