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Discovering the causes of cancer and the means of prevention
 

Scientific Highlights November 2018 - February 2019

, by DCEG Staff

Brain

Diet

Data on over 1.2 million participants in three large prospective studies showed little, if any, association between major food groups, nutrients, or common healthy dietary patterns, and glioma incidence. (Kuan AS, Green J, Kitahara CM, et al. Diet and risk of glioma: Combined analysis of three large prospective studies in the UK and USA. Neuro Oncol 2019; Epub Jan 23)

Breast

BRCA1 and BRCA2 Variants Resource

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. The BRCA Exchange is an international resource that provides an informed and current understanding of the impact of genetic variation on cancer risk across the cancer predisposition genes, BRCA1 and BRCA2. Reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, called The BRCA Exchange, to provide a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. (Cline MS, Liao RB, Parsons MT, et al. BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2. PLoS Genet 2018; For more information, read BRCA Exchange Aggregates Data on Thousands of BRCA1 and BRCA2 Variants in Research News & Highlights.

Estrogen Metabolism

A case-control study of estrogen metabolism and risk of ovarian and endometrial cancer was conducted within the Women’s Health Initiative Observational Study. The data suggest that estrogen metabolism may differ for use of menopausal hormone therapy with estrogen alone compared to estrogen and progestin users, with estrogen alone inducing estrogen metabolism away from the 16α‐pathway and toward the 2‐pathway, a pattern shown to reduce breast cancer risk in postmenopausal women. However, the magnitude of observed differences between these groups is small, and it is not known if this metabolic pattern persists after cessation of hormone therapy. (Falk RT, Manson JE, Barnabei VM, et al. Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone? Int J Cancer 2019; Epub 2018 Nov 1)

Maternal Hormones and Angiogenic Factors

Investigators conducted a prospective breast cancer case-control study among women in the Avon Longitudinal Study of Parents and Children and Norwegian Mother and Child Cohort Study to evaluate whether breast cancer risk associated with pregnancy characteristics may be mediated by maternal hormones or angiogenic factors. There was no strong evidence of associations between maternal estradiol, testosterone, androstenedione, human chorionic gonadotropin, prolactin, placental growth factor, or soluble fms-like tyrosine kinase-1 and subsequent maternal breast cancer risk. (Cornish R, Staff AC, Boyd A, et al. Maternal reproductive hormones and angiogenic factors in pregnancy and subsequent breast cancer risk. Cancer Causes Control 2019; Epub 2018 Dec 1)

Polygenic Risk Scores

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Investigators developed PRSs, optimized for prediction of estrogen receptor-specific disease, from the largest available genome-wide association dataset and empirically validated the PRSs in prospective studies. Goodness-of-fit tests indicated that the PRS was well calibrated and predicted disease risk accurately in the tails of the distribution. (Mavaddat N, Michailidou K, Dennis J, et al. Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. Am J Hum Genet 2019; Epub 2018 Dec 13)

Childhood Cancer

International Consortium

The International Childhood Cancer Consortium (IC4), a consortium of pregnancy and birth cohorts, was established to utilize prospective, pre-diagnostic exposure assessments and biological samples for epidemiologic research. Eligibility criteria, follow-up methods and identification of pediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonization methods, biological samples potentially available for research, the role of the I4C data and biospecimen coordinating centers and statistical approaches used in pooled analyses. Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388,120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627,500 additional projected mother-child pairs within five years. (Tikellis G, Dwayer T, Paltiel O, et al. The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers. Paediatr Perinat Epidemiol 2019)

Colorectum

Circulating Inflammation Markers

A comparison of serum levels of 78 inflammation markers between 171 pathologically confirmed colorectal adenoma cases (including 48 incident cases) and 344 controls within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial identified 14 markers associated with risk of adenoma overall; three of these were also associated with incident adenoma: CCL20, GRO, and insulin. (Huang WY, Berndt SI, Shiels MS, et al. Circulating inflammation markers and colorectal adenoma risk. Carcinogenesis 2019; Epub Feb 7)

Increasing Incidence in Rural Kenya

PERSPECTIVES – Parker RK, Ranketi SS, McNelly C, et al. Colorectal cancer is increasing in rural Kenya: Challenges and perspectives. Gastrointest Endosc 2019; Epub 2018 Dec 10.

Neighborhood Socioeconomic Status

A growing body of research has demonstrated that individuals who live in neighborhoods with more severe socioeconomic deprivation may have higher risks for colorectal cancer (CRC). However, previous studies have examined neighborhood socioeconomic status (SES) at only one point in time. Data from the NIH-AARP Diet and Health study suggest that exposure to consistently low SES neighborhoods and/or a decrease in neighborhood SES over a period of time may be associated with higher risks of CRC. (Zhang D, Matthew CE, Powell-Wiley TM, Xiao Q. Ten-year change in neighborhood socioeconomic status and colorectal cancer. Cancer 2019; 2018 Nov 13)

Research Gaps

MEETING REPORT - Gunter MJ, Alhomoud S, Arnold M, et al. Meeting Report from the joint IARC-NCI international cancer seminar series: A focus on colorectal cancer. Ann Oncol 2019: Epub Feb 5.

Endometrium

Folate-Mediated One-Carbon Metabolism

Investigators used data from the large, prospective NIH-AARP Diet and Health Study to evaluate endometrial cancer risk associated with calorie-adjusted dietary intake of several B vitamins and methionine. Increased risk was associated with greater consumption of dietary total folate, natural folate, B2, B6 and B12. Risks for the highest intakes of B2 and methionine were evident among women who were overweight/obese, but not among normal/underweight women. The findings indicate that one-carbon metabolism plays a role in endometrial carcinogenesis and exploration of this role in tissue and cellular biology studies is warranted. (Lu J, Trabert B, Liao LM, et al. Dietary intake of nutrients involved in folate-mediated one-carbon metabolism and risk for endometrial cancer. Int J Epidemiol 2018; Epub Dec 13)

Gallbladder

Statin Use

The association between statin use and risk of biliary tract cancers (BTC) was evaluated in data from the UK Clinical Practice Research Datalink. Current statin use versus non-use was associated with a reduced risk of all BTCs combined, with reduced risks most pronounced among long-term users, as indicated by increasing number of prescriptions and cumulative dose of statins, and among persons with diabetes. (Liu Z, Alsaggaf R, McGlynn KA, et al. Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink. Gut 2018; Epub Nov 17)

Trends in the U.S.

A recent U.S. study reported increasing gallbladder cancer (GBC) incidence among people younger than 45 years and blacks; however, it did not examine trends for other biliary tract sites. Data from the North American Association of Central Cancer Registries showed found that GBC incidence rates declined among women and all racial/ethnic groups except for non-Hispanic blacks, among whom rates increased. Although GBC rates increased among 18- to 44-year-olds, they decreased among people 45 years old or older. Intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma rates steadily increased across sex and racial/ethnic groups. Ampulla of Vatar cancer incidence rates increased among younger adults but not older adults. These findings highlight the need for large pooling projects to evaluate BTC risk factors by anatomic site. (Van Dyke AL, Shiels MS, Jones GS, et al. Biliary tract cancer incidence and trends in the United States by demographic group, 1999-2013. Cancer 2019; Epub Jan 15)

Genetics

Allele-specific Somatic Copy Number Alteration Analysis

Somatic copy number alteration (SCNA) is a common feature of the cancer genome and is associated with cancer etiology and prognosis. The allele-specific SCNA analysis of a tumor sample aims to identify the allele-specific copy numbers of both alleles, adjusting for the ploidy and the tumor purity. Next-generation sequencing platforms produce abundant read counts at the base-pair resolution across the exome or whole genome, which is susceptible to hypersegmentation, a phenomenon where numerous regions with very short length are falsely identified as SCNA. The authors propose hsegHMM, a hidden Markov model approach that accounts for hypersegmentation for allele-specific SCNA analysis. hsegHMM provides statistical inference of copy number profiles by using an efficient E-M algorithm procedure. Through simulation and application studies, they found that hsegHMM handles hypersegmentation effectively with a t-distribution as a part of the emission probability distribution structure and a carefully defined state space. hsegHMM is robust, provides the quantification of uncertainty in identifying allele-specific SCNAs over the entire chromosomes, and performs better than FACETS when read depth (coverage) is uneven across the genome. (Choo-Wosoba H, Albert PA, Zhu B. hsegHMM: Hidden Markov model-based allele-specific copy number alteration analysis accounting for hypersegmentation. BMC Bioinformatics 2018)

Gene-Supplement Interactions

To learn more about the contributions of genetic variation to the efficacy and safety of vitamin supplements, investigators used data from two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic analysis of catechol-O-methyltransferase (COMT) revealed that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements used for health promotion. (Hall KT, Buring JE, Mukamal KJ, et al. COMT and alpha-tocopherol effects in cancer prevention: Gene-supplement interactions in two randomized clinical trials. J Natl Cancer Inst 2019; Epub Jan 8)

Mosaic Y Loss

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes has lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Evidence from the UK Biobank indicates mLOY is moderately associated with increased risk of select tumors, most notably lung cancer (Loftfield E, Zhou W, Yeager M, et al. Mosaic Y loss is moderately associated with solid tumor risk. Cancer Res 2019; Epub 2018 Dec 3)

Prevalence of TP53 Variants

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. This study evaluated the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n = 138,632). Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400–865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype. (de Andrade KC, Frone MN, Wegman-Ostrosky T, et al. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis. Hum Mutat 2019; Epub 2018, Nov 19)

Variants in the ACMG Secondary Findings Genes

Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. This study investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort and in cancer-free ethnicity-matched controls. Eight P/LP unique variants (8 individuals; 0.8%) were observed among controls and 11 P/LP unique variants (14 individuals; 1.2%) among cases, a non-significant difference. A total of 115 variants of unknown significance (VUS) were reviewed, in a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. This work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls. (Kim J, Luo W, Wang M, et al. Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls. Genome Med 2018;10:99)

Infections and Cancer

Hepatitis B Virus

Hepatitis B virus (HBV) infection causes hepatocellular carcinoma (HCC). Associations with other cancers are not established. Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database were used to evaluate associations between HBV infections and other cancers. HBV prevalence was positively associated with cancers of the stomach, anus, intrahepatic bile ducts, and nasopharynx, as well as myelodysplastic syndrome and diffuse large B-cell lymphoma. Inverse associations were observed with female breast and prostate cancers and chronic lymphocytic leukemia. (Mahale P, Engels EA, Koshiol J. <a data-cke-saved-href=" pubmed="" www.ncbi.nlm.nih.gov="">Hepatitis B virus infection and the risk of cancer in the elderly U.S. population. Int J Cancer 2019; Epub Nov 28)

Leukemia

Sex-related DNA Methylation

This study investigated whether differences in DNA methylation patterns contributes to the sex-related difference of chronic lymphocytic leukemia (CLL) risk. Using the HumanMethylation450 BeadChip, the genome-wide DNA methylation pattern was profiled in CD19+ B cells from 48 CLL patients (29 women, 19 men) and 28 healthy people (19 women, 9 men). There were 1043 sex-related differentially methylated positions (DMPs) related to CLL, 56 of which are located on autosomes and 987 on the X chromosome. Using published B cell RNA-sequencing data, investigators found 18 genes covered by the DMPs also have different expression levels in male and female CLL patients. Among them, TRIB1, an autosome gene, has been shown to promote tumor growth by suppressing apoptosis. This study represents the first epigenome-wide association study that investigates the sex-related differences in cancer and indicates that DNA methylation differences might contribute to the sex-related difference in CLL risk. (Lin S, Liu Y, Golding LR, et al. Sex-related DNA methylation differences in B cell chronic lymphocytic leukemia. Biol Sex Differ 2019; Jan 7)

Liver

Bacterial Translocation

Elevated systemic exposure to gut-derived bacterial products has been associated with hepatic inflammation and chronic liver diseases, potentially increasing the risk of liver cancer. However, only one prior study prospectively examined exposure to bacterial products in the circulation and risk of liver cancer, with a relatively limited coverage of biomarkers. In a prospective cohort of Finnish male smokers, the risk of liver cancer was assessed in relation to a panel of biomarkers for bacterial translocation. Anti-flagellin immunoglobulin (Ig) A and anti-lipopolysaccharide IgA were significantly associated with risk of liver cancer. (Yang B, Petrick JL, Thistle JE, et al. Bacterial translocation and risk of liver cancer in a Finnish cohort. Cancer Epidemiol Biomarkers Prev 2019; Epub Jan 2)

Autoimmune Conditions

Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database were used to evaluate associations between autoimmune conditions and hepatobiliary cancers. Sixteen conditions were associated with at least one hepatobiliary cancer. The strongest risk estimates were for primary biliary cholangitis with hepatocellular carcinoma and primary sclerosing cholangitis with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of Vater cancer. Associations with hepatobiliary-related conditions as a group were observed across nearly all cancer sites. These findings support a shared immuno-inflammatory etiology to these cancers. (McGee EE, Castro FA, Engels EA, et al. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly U.S. adults. Int J Cancer 2019; Epub 2018 Nov 8)

Lymphoma

Malaria

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. The authors investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria. eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk. (Derkach A, Otim I, Pfeiffer RM, et al. Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studies. EBioMedicine 2019; Epub 2018 Dec 20)

Methods

Allele-specific Somatic Copy Number Alteration Analysis

Somatic copy number alteration (SCNA) is a common feature of the cancer genome and is associated with cancer etiology and prognosis. The allele-specific SCNA analysis of a tumor sample aims to identify the allele-specific copy numbers of both alleles, adjusting for the ploidy and the tumor purity. Next-generation sequencing platforms produce abundant read counts at the base-pair resolution across the exome or whole genome, which is susceptible to hypersegmentation, a phenomenon where numerous regions with very short length are falsely identified as SCNA. The authors propose hsegHMM, a hidden Markov model approach that accounts for hypersegmentation for allele-specific SCNA analysis. hsegHMM provides statistical inference of copy number profiles by using an efficient E-M algorithm procedure. Through simulation and application studies, they found that hsegHMM handles hypersegmentation effectively with a t-distribution as a part of the emission probability distribution structure and a carefully defined state space. hsegHMM is robust, provides the quantification of uncertainty in identifying allele-specific SCNAs over the entire chromosomes, and performs better than FACETS when read depth (coverage) is uneven across the genome. (Choo-Wosoba H, Albert PA, Zhu B. hsegHMM: Hidden Markov model-based allele-specific copy number alteration analysis accounting for hypersegmentation. BMC Bioinformatics 2018)

Mortality

Premature Mortality

Between 2000 and 2015, 9.5 million premature deaths occurred among 25-64-year-olds in the U.S., nearly 500,000 from drug poisonings. In comparing the periods 2000-2003 and 2012-2015, the researchers observed sharp increases in death rates from drug poisoning in counties throughout the country: wealthier and poorer counties, urban and rural counties, and among whites, blacks and Latinos. Although drug poisoning death rates increased more rapidly in poorer and rural counties, far more deaths occurred in metropolitan counties (76% of drug overdose deaths) than in rural counties (1% of drug overdose deaths), reflecting the larger population size of cities. Widespread public health interventions are needed to address this public health emergency. (Shiels MS, Berrington de González A, Best AF, et al. <a data-cke-saved-href=" pubmed="" www.ncbi.nlm.nih.gov="">Premature mortality from all causes and drug poisonings in the U.S.A. according to socioeconomic status and rurality: An analysis of death certificate data by county from 2000-15. Lancet Public Health 2019). For more information, read Drug Overdose Deaths a National Problem, not Limited to Poor, Rural Counties in Research News & Highlights.

Trends in Infant and Youth Mortality

This descriptive study analyzed data from the U.S. National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. Mortality rates in the U.S. have generally declined for infants and youth from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury, and homicides. However, U.S. mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among U.S. adolescents and young adults. (Khan SQ, Berrington de Gonzalez A, Best AF, et al. Infant and youth mortality trends by race/ethnicity and cause of death in the United States. JAMA Pediatr 2018) For more information, read Pediatric Mortality Decreases in U.S., but Rates Still Higher than Canada and U.K. in Research News & Highlights.

Ovary

Androgens

Using highly sensitive LC-MS/MS assays, the authors evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative Observational Study. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer, but not serous tumors. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. (Trabert B, Michels KA, Anderson GL, et al. Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study. Int J Cancer 2019; Epub Jan 26)

Pancreas

Genetic Susceptibility

The authors conducted a large agnostic pathway-based meta-analysis of genome-wide association studies’ data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) among 9,040 cases and 12,496 controls, integrating it with functional annotation and expression quantitative trait loci (eQTL) analysis. The strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. Investigators identified and validated rs876493 and three correlating single-nucleotide polymorphisms (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. (Walsh N, Zhang H, Hyland PL, et al. Agnostic pathway/gene set analysis of genome-wide association data identifies associations for pancreatic cancer. J Natl Cancer Inst 2018; Epub Dec 12)

Skin

Whole Exome Sequencing

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships. The authors evaluated 18 NBCCS families in the National Cancer Institute (NCI) studies plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). This is the largest study to date to assemble and characterize NBCCS PTCH1‐associated mutations and clinical data using targeted PTCH1 sequencing, aCGH, SNP array data, WES, and HGMD data extraction. PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. A significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions, with suggestive associations between falx cerebri calcification and all transmembrane domains and severe outcomes and gross deletion-insertions. Overall, 89% of NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. (Gianferante DM, Rotunno M, Dean M, et al. Whole-exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data. Mol Genet Genomic Med 2018)

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