PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

In a clinical setting, next-generation sequencing (NGS) approaches for the enrichment and resequencing of DNA targets may have limitations in throughput, cost, or accuracy. We evaluated an NGS workflow for targeted DNA sequencing for mutation detection. Targeted sequence data of the BRCA1 and BRCA2 genes, generated using a PCR-based, multiplexed NGS approach using the SOLiD 4 (n = 24) and Ion Torrent PGM (n = 20) next-generation sequencers, were evaluated against sequence data obtained by Sanger sequencing. The overall sensitivity for SOLiD and PGM were 97.8% (95% CI = 94.7 to 100.0) and 98.9% (95% CI = 96.8 to 100.0) respectively. The specificity for the SOLiD platform was high, at 100.0% (95% CI = 99.3 to 100.0). PGM correctly identified all 3 indels, but 68 false-positive indels were also called. Equimolar normalization of amplicons was not necessary for successful NGS. Both platforms are highly amenable to scale-up, potentially reducing the reagent cost for BRCA testing to

The present study aimed to identify polymorphic genes encoding carbonyl reductases (CBR1, CBR3) and investigate their influence on doxorubicin disposition in Asian breast cancer patients (n = 62). Doxorubicin (60 mg/m 2 ) was administered every 3 weeks for four to six cycles and the pharmacokinetic parameters were estimated using non-compartmental analysis (WinNonlin). The Mann-Whitney U-test was used to assess genotypic-phenotypic correlations. (1) The phase I and II enzymes are expressed abundantly in hepatic tissues and display large interindividual variations in their metabolic capacities toward a wide array of therapeutic agents.The CBR are ubiquitously expressed monomeric NADPHdependent cytosolic enzymes that catalyze the reduction of chemically diverse substrates such as aldehydes, ketones, quinones, and other xenobiotics.(2,3) Apart from the metabolism of endogenous compounds and drug detoxification, CBR are also assumed to participate in cellular processes such as signal transduction, (4) apoptosis,mutagenesis,carcinogenesis,and drug resistance.(8) Four CBR isoforms (CBR1, CBR2, CBR3, and CBR4) that were initially assigned to the aldo-keto reductase (AKR) family are now classified under the family of short-chain dehydrogenases and represent one of the largest protein families identified to date.(9) CBR1 is the major carbonyl reductase and is expressed widely in different tissues. The CBR1 gene is mapped to chromosome 21q22.12, has three exons spanning 3.3 kb, and encodes a 30-kDa monomeric protein comprising 277 amino acids. The CBR1 gene lacks a CAAT and TATA box and contains a GC-rich island extending into the first exon, a structure characteristic of genes having a housekeeping function.(4) The identified substrates of human CBR1 include endogenous compounds (prostaglandins and steroids) and drugs such as loxoprofen, (4) metyrapone, (10) haloperidol, (11) bromoperidol,timirepone, (13) and doxorubicin. (14) CBR2 has low sequence identity with CBR1 and has not been identified in human tissues. The CBR3 gene contains three exons spanning a region of 11.2 kb and has a 72% sequence similarity with CBR1. It is located 62 kb telomeric to the CBR1 gene. Although widely expressed, the relative expression of CBR3 is much lower than CBR1 in most of the tissues analyzed.(15) The CBR4 gene is located on human chromosome 4 (4q32.3) and encodes a protein composed of 237 amino acids, but its enzymatic properties and tissue distribution remain unknown. (15) To date, there are limited studies investigating the influence of genetic polymorphisms in the CBR genes on the pharmacokinetics and pharmacodynamics of drugs. Avramopoulos et al. identified the CBR1 3′-untranslated region (UTR) G>A transition for the linkage mapping of the CBR gene on chromosome 21. (16) However, the effect of the polymorphism on enzyme activity and tissue expression is not known. Gonzalez-Covarrubias et al. reported the V88I (262G>A, rs1143663), L73L (312G>C, rs25678), A209A (720C>T, rs20572), and V231V (786G>A, rs2230192) polymorphisms by scree...

Genetic testing for germline mutations in breast cancer predisposition genes can potentially identify individuals at a high risk of developing breast and/or ovarian cancer. There is a paucity of such mutational information for Asians. Panel testing of 25 cancer susceptibility genes and BRCA1/2 deletion/duplication analysis was performed for 220 Asian breast cancer patients or their family members referred for genetics risk assessment. All 220 participants had at least one high-risk feature: having a family history of breast and/or ovarian cancer in first- and/or second-degree relatives; having breast and ovarian cancer in the same individual or bilateral breast cancer; having early-onset breast cancer or ovarian cancer (⩽40 years of age). We identified 67 pathogenic variants in 66 (30.0%) patients. Of these, 19 (28.3%) occurred in BRCA1, 16 (23.9%) in BRCA2, 7 (10.4%) in PALB2, 6 (9.0%) in TP53, 2 (3.0%) in PTEN, 2 (3.0%) in CDH1 and 15 (22.4%) in other predisposition genes. Notably, 47.8% of pathogenic variants were in non-BRCA1/2 genes. Of the 66 patients with pathogenic mutations, 63.6% (42/66) were under the age of 40 years. Family history of breast and/or ovarian cancer is enriched in patients with BRCA1/2 pathogenic variants but less predictive for non-BRCA1/2 related pathogenic variations. We detected a median of three variants of unknown significance (VUS) per gene (range 0–21). Custom gene panel testing is feasible and useful for the detection of pathogenic mutations and should be done in the setting of a formal clinical cancer genetics service given the rate of VUS.