Tumour Infiltrating Lymphocytes (TILs) and immune composition in breast cancer patients from Kenya: Spatial distributions and associations with risk factors and tumour characteristics.

Background: The immune landscape of breast cancer (BC) in patients from Sub Saharan Africa is understudied. Our aims were to describe the distribution of Tumour Infiltrating Lymphocytes (TILs) within the intratumoural stroma (sTILs) and the leading/invasive edge stroma (LE-TILs), and to evaluate TILs across BC subtypes with established risk factors and clinical characteristics in Kenyan women.

Methods: Visual quantification of sTILs and LE-TILs were performed on Haematoxylin and eosin -stained pathologically confirmed BC cases based on the International TIL working group guidelines.

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.

Tumor-Associated Stromal Cellular Density as a Predictor of Recurrence and Mortality in Breast Cancer: Results from Ethnically Diverse Study Populations.

Purpose: Tumor-associated stroma is comprised of fibroblasts, tumor-infiltrating lymphocytes (TIL), macrophages, endothelial cells, and other cells that interactively influence tumor progression through inflammation and wound repair. Although gene-expression signatures reflecting wound repair predict breast cancer survival, it is unclear whether combined density of tumor-associated stromal cells, a morphologic proxy for inflammation and wound repair signatures on routine hematoxylin and eosin (H&E)-stained sections, is of prognostic relevance.

Methods: By applying machine learning to digitized H&E-stained sections for 2,084 breast cancer patients from China ( = 596; 24-55 years), Poland ( = 810; 31-75 years), and the United States ( = 678; 55-78 years), we characterized tumor-associated stromal cellular density (SCD) as the percentage of tumor-stroma that is occupied by nucleated cells.

Nighttime eating and breast cancer among Chinese women in Hong Kong.

Background: A novel line of research suggests that eating at nighttime may have several metabolic consequences that are highly relevant to breast cancer. We investigated the association between nighttime eating habits after 10 p.m.

Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.

Purpose: The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+) type.

Methods: Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings) were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age) and type of relative affected with the disease.

ERβ splice variant expression in four large cohorts of human breast cancer patient tumors.

Though the role of Estrogen Receptor (ER)α in breast cancer has been studied extensively, there is little consensus about the role of alternative ER isoform ERβ in breast cancer biology. ERβ has significant sequence homology to ERα but is located on a different chromosome and maintains both overlapping and unique functional attributes. Five variants exist, resulting from alternative splicing of the C-terminal region of ERβ.

Constitutional promoter methylation and risk of familial melanoma.

Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples.

Variants associated with susceptibility to pancreatic cancer and melanoma do not reciprocally affect risk.

Background: Melanoma cases may exist in pancreatic cancer kindreds, whereas there is increased risk of pancreatic cancer in familial melanoma. The two cancers may share genetic susceptibility variants in common.

Methods: Three dbGaP (datasets in Genotypes and Phenotypes)-deposited GWAS (genome-wide association study) datasets (MD Anderson melanoma, PanScan 1, and PanScan 2 for pancreatic cancer) were used.

Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations.

Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A-) for 233 tagging SNPs in 21 genes at 9p21.

Association of human leukocyte antigens with nasopharyngeal carcinoma in high-risk multiplex families in Taiwan.

An association between specific human leukocyte antigens (HLA) alleles and nasopharyngeal carcinoma (NPC) has been reported for sporadic NPC, but studies of familial NPC are lacking. We evaluated this association with familial NPC in a study of 301 NPC cases and 1010 family and community controls from Taiwan. Class I HLA alleles were characterized using a sequence-based typing protocol.

Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.

CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM), but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A-) for 1,536 SNPs in 152 genes involved in DNA repair, apoptosis and immune response pathways.

Estimating age-specific breast cancer risks: a descriptive tool to identify age interactions.

Objective: Clarifying age-specific female breast cancer risks and interactions may provide important etiologic clues.

Method: Using a population-based case-control study in Poland (2000-2003) of 2,386 incident breast cancer cases and 2,502 control subjects aged 25-74 years, we estimated age-specific breast cancer incidence rates according to risk factors.

Results: Breast cancer risks were elevated among women with positive family history (FH), younger age at menarche, older age at first full-term birth, nulliparity, exogenous hormonal usage, and reduced physical activity (PA).

Construction and validation of tissue microarrays of ductal carcinoma in situ and terminal duct lobular units associated with invasive breast carcinoma.

Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.

Genetic variation of Cytochrome P450 1B1 (CYP1B1) and risk of breast cancer among Polish women.

Four single nucleotide polymorphisms (SNPs) in CYP1B1 (Ex2 + 143 C > G, Ex2 + 356 G > T, Ex3 + 251 G > C, Ex3 + 315 A > G) cause amino acid changes (R48G, A119S, L432V and N453S, respectively) and are associated with increased formation of catechol estrogens; however, epidemiologic evidence only weakly supports an association between these variants and breast cancer risk. Because genetic variability conferring increased susceptibility could exist beyond these putative functional variants, we comprehensively examined the common genetic variability within CYP1B1. A total of eight haplotype-tagging (ht)SNPs (including Ex3 + 315 A > G), in addition to two putatively functional SNPs (Ex2 + 143 C > G and Ex3 + 251 G > C), were selected and genotyped in a large case-control study of Polish women (1995 cases and 2296 controls).

Linkage analysis of the GAW14 simulated dataset with microsatellite and single-nucleotide polymorphism markers in large pedigrees.

Recent studies have suggested that a high-density single nucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for gene mapping by linkage. The focus of this study was to compare results obtained from linkage analyses involving extended pedigrees with STR and single-nucleotide polymorphism (SNP) marker sets. We also wanted to compare the performance of current linkage programs in the presence of high marker density and extended pedigree structures.

Identification of susceptibility loci for complex diseases in a case-control association study using the Genetic Analysis Workshop 14 dataset.

Although current methods in genetic epidemiology have been extremely successful in identifying genetic loci responsible for Mendelian traits, most common diseases do not follow simple Mendelian modes of inheritance. It is important to consider how our current methodologies function in the realm of complex diseases. The aim of this study was to determine the ability of conventional association methods to fine map a locus of interest.

Evaluation of risk factors for nasopharyngeal carcinoma in high-risk nasopharyngeal carcinoma families in Taiwan.

A study of nasopharyngeal carcinoma (NPC) families with two or more affected members was conducted in Taiwan (265 families with 2,444 individuals, 502 affected and 1,942 unaffected) to determine the association between NPC and potential etiologic factors in NPC high-risk families. Similar to results from a previous case-control study in Taiwan, Guangdong salted fish consumption during childhood, exposure to wood, and betel nut consumption were all associated with elevated NPC risk using conditional logistic regression, although these associations were not as strong as in the case-control study possibly due to shared environment among family members. Risk associated with cumulative wood exposure and salted fish consumption before age 10 was stronger in families with early NPC age-onset [odds ratio (OR(wood)), 5.

Corroboration of a familial chordoma locus on chromosome 7q and evidence of genetic heterogeneity using single nucleotide polymorphisms (SNPs).

Chordoma, a rare bone tumor originating from notochordal remnants, has a genetic predisposition in some families. Previously, we performed linkage analysis using microsatellite (STR) markers on 3 unrelated chordoma kindreds (16 patients with chordoma) and reported significant evidence for linkage to chromosome 7q33 (Z(max) = 4.78) with a minimal disease gene region of 11 cM.

Genomic regions linked to alcohol consumption in the Framingham Heart Study.

Background: Pedigree, demographic, square-root transformed maximum alcohol (SRMAXAPD) and maximum cigarette (MAXCPD) consumption, and genome-wide scan data from the Framingham Heart Study (FHS) were used to investigate genetic factors that may affect alcohol and cigarette consumption in this population-based sample.

Results: A significant sister:sister correlation greater than spouse correlation was observed for MAXCPD only. Single-point sib-pair regression analysis provided nominal evidence for linkage of loci to both SRMAXAPD and MAXCPD consumption traits, with more significant evidence of linkage to SRMAXAPD than to MAXCPD.