Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

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cral melanoma is a rare melanocytic tumor that arises on the non-hair-bearing skin of the palms, soles, and nail beds. 1 Unlike cutaneous melanoma, acral melanoma is not linked to UV radiation exposure; it exhibits a much lower point mutation burden than cutaneous melanoma but a higher frequency of structural variants and copy number alterations. 2,3 The incidence of acral melanoma is uniform across all populations, making it the most common melanoma subtype in individuals of African, Asian, and Hispanic descent. 1 Acral melanomas differ in their mutational profiles from cutaneous melanomas, with a lower incidence of BRAF mutations (18%) and NF1 mutations (11%) and the presence of mutations in TYRP1 (8%) and NOTCH2 (4%) and amplification/ mutation in the receptor tyrosine kinase c-KIT (approximately 2%-3%). 3 Acral melanomas with BRAF mutations harbor fewer genomic amplifications and are more common in patients with European ancestry, possibly constituting a unique subset. 4 Melanocytic nevi are benign proliferations of melanocytes; melanomas sometimes arise in a small proportion of melanocytic nevi. [5][6][7] Genomic analyses have shown that 100% of nevi on sun-exposed skin harbor mutually exclusive mutations in melanoma driver oncogenes, such as BRAF and NRAS. [8][9][10] Although the development of nevi has been linked to sun exposure, 10,11 they can also arise on skin with low levels of UV radiation exposure, such as the palms and soles. At this time, little is known about the mutational profiles of acral nevi, which arise on skin with little UV radiation exposure. Methods Patient SamplesThis study was approved by the University of South Florida institutional review board (protocol No. PRO00036516). Deidentified archival samples were collected under a waiver of informed consent under the Common Rule (45 CFR 46). After institutional review board approval, the pathology databases at 2 institutions were queried for a diagnosis containing the words melanocytic nevus at any acral location (palm, sole, finger, toe, foot, hand). Slides were reviewed and diagnoses verified by the study pathologist (J.L.M.); 49 of 50 cases with greater than 10% nevus cellularity and 1 case with 5% nevus cellularity were submitted for analysis. DNA SequencingTargeted DNA sequencing was performed on 151 cancerassociated genes (eTable 1 in the Supplement) (Agilent Sure-Select XT ClearSeq Comprehensive Cancer Panel). For each sample, 75-base paired-end sequence reads were generated IMPORTANCE Acral skin may develop nevi, but their mutational status and association with acral melanoma is unclear.OBJECTIVE To perform targeted next-generation sequencing on a cohort of acral nevi to determine their mutational spectrum.DESIGN, SETTING, AND PARTICIPANTS Acral nevi specimens (n = 50) that had been obtained for diagnostic purposes were identified from the pathology archives of a tertiary care academic cancer center and a university dermatology clinic. Next-generation sequencing was performed on DNA extracted from the specimens, and mutations calle...

Phenotyping of immune cell subsets in clinical trials is limited to well-defined phenotypes, due to technological limitations of reporting flow cytometry multi-dimensional phenotyping data. We developed a multi-dimensional phenotyping analysis tool and applied it to detect nitric oxide (NO) levels in peripheral blood immune cells before and after adjuvant ipilimumab co-administration with a peptide vaccine in melanoma patients. We analyzed inhibitory and stimulatory markers for immune cell phenotypes that were felt to be important in the NO analysis. The pipeline allows visualization of immune cell phenotypes without knowledge of clustering techniques and to categorize cells by association with relapse-free survival (RFS). Using this analysis, we uncovered the potential for a dichotomous role of NO as a pro-and anti-melanoma factor. NO was found in subsets of immune-suppressor cells associated with shorter-term (≤1 year) RFS, whereas NO was also present in immune-stimulatory effector cells obtained from patients with significant longer-term (>1 year) RFS. These studies provide insights into the cell-specific immunomodulatory role of NO. The methods presented herein can be applied to monitor the pro-and anti-tumor effects of a variety of immune-based therapeutics in cancer patients. Clinical Trial Registration Number: NCT00084656 (https://clinicaltrials.gov/ct2/ show/NCT00084656).

Motivation Missingness in label-free mass spectrometry is inherent to the technology. A computational approach to recover missing values in metabolomics and proteomics datasets is important. Most existing methods are designed under a particular assumption, either missing at random or under the detection limit. If the missing pattern deviates from the assumption, it may lead to biased results. Hence, we investigate the missing patterns in free mass spectrometry data and develop an omnibus approach GMSimpute, to allow effective imputation accommodating different missing patterns. Results Three proteomics datasets and one metabolomics dataset indicate missing values could be a mixture of abundance-dependent and abundance-independent missingness. We assess the performance of GMSimpute using simulated data (with a wide range of 80 missing patterns) and metabolomics data from the Cancer Genome Atlas breast cancer and clear cell renal cell carcinoma studies. Using Pearson correlation and normalized root mean square errors between the true and imputed abundance, we compare its performance to K-nearest neighbors’ type approaches, Random Forest, GSimp, a model-based method implemented in DanteR and minimum values. The results indicate GMSimpute provides higher accuracy in imputation and exhibits stable performance across different missing patterns. In addition, GMSimpute is able to identify the features in downstream differential expression analysis with high accuracy when applied to the Cancer Genome Atlas datasets. Availability and implementation GMSimpute is on CRAN: https://cran.r-project.org/web/packages/GMSimpute/index.html. Supplementary information Supplementary data are available at Bioinformatics online.