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Discovering the causes of cancer and the means of prevention

Scientific Highlights July - October 2017

Posted on September 26, 2017

Updated February 2, 2018

Cancer Topics

Bone

Therapeutic Genomic Targets

REVIEW: Savage SA, Mirabello L. Bone cancer: Is the osteosarcoma genome targetable? Nat Rev Endocrinol 2017; Epub Aug 4.

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Breast

Estrogen Receptor-negative and BRCA1

Members of the OncoArray Network conducted a genome-wide association study using 21,468 estrogen receptor (ER)-negative breast cancer cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. Ten variants at nine new loci were identified at p< 5×10-8 in addition to replication or consistent associations for most variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS. The total 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer. (Milne RL, Kuchenbaecker KB, Michailidou K, et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 2017; Epub Oct 23). For more information, read International consortium adds 72 genetic variants to list of known breast cancer associations in Research News & Highlights.

Genetic Susceptibility

A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry, and 14,068 cases and 13,104 controls of East Asian ancestry was conducted using the OncoArray chip. The study identified 65 new loci that are associated with overall breast cancer risk at p< 5×10-8. There was a strong overlap between candidate target genes and somatic driver genes in breast tumors. In addition, the heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was two- to-five-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. (Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature 2017; Epub Oct 23). For more information, read International consortium adds 72 genetic variants to list of known breast cancer associations in Research News & Highlights.

Thyroid Dysfunction and Mortality Risk

A large, prospective study revealed that women with hyperthyroidism had an elevated risk of breast cancer mortality after 60 years of age (hazard ratio = 2.04) compared to women without thyroid disease. Women with hypothyroidism were at increased risk for mortality from diabetes mellitus, cardiovascular disease, and cerebrovascular disease. (Journy NMY, Bernier MO, Doody MM, et al. Hyperthyroidism, hypothyroidism, and cause-specific mortality in a large cohort of women. Thyroid 2017; Epub Jul 16)

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Cervix

Colposcopy Standards

Results from the DCEG-designed and -led Biopsy Study to Improve Detection of Cervical Cancer provided a large portion of the evidence used by the American Society for Colposcopy and Cervical Pathology to create the first U.S. recommendations for colposcopy practice, a cervical cancer prevention technique in which the cervix is inspected for signs of cancer or precancer and biopsied. The recommendations cover terminology, risk-based colposcopy, colposcopy procedures, and colposcopy adjuncts, and are an important step toward raising the standard of colposcopy services delivered to women in the U.S. (Wentzensen N, Massad LS, Mayeaux EJ Jr, et al. Evidence-Based Consensus Recommendations for Colposcopy Practice for Cervical Cancer Prevention in the United States. J Low Genit Tract Dis 2017). For more information, read Research from DCEG Study Informs New Cervical Cancer Prevention Standards in Research News & Highlights.

Human Papillomavirus

A novel HPV whole-genome sequencing technique was used to evaluate an exceptionally large collection of 5,570 HPV 16-positive cervical samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. Among thousands of unique HPV 16 genomes, very few women shared the identical HPV 16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV 16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, the E7 oncogene was devoid of variants in precancer/cancer samples, compared to controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV 16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research. (Mirabello L, Yeager M, Yu K, et al. HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis. Cell 2017). For more information, read Whole-Genome Sequencing of HPV 16 Reveals New Criterion for Carcinogenicity in Research News & Highlights.

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Colorectum

Ghrelin

A case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study showed that low-serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw, and a decreased risk for developing colorectal cancer more than 20 years after blood draw, suggesting that ghrelin concentrations may vary across the carcinogenic process. (Murphy G, Cross AJ, Dawsey, et al. Serum ghrelin is associated with risk of colorectal adenocarcinomas in the ATBC study. Gut 2017; Epub Aug 16). For more information, read Serum ghrelin concentration linked to colorectal cancer in Research News & Highlights.

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Esophagus

Epidemiology

Review: Abnet CC, Arnold M, Weit WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 2017; Epub Aug17.

Genetic Loci Associated with Family History

Following up on a genome-wide association study (GWAS) of esophageal squamous cell carcinoma (ESCC) among Han Chinese, investigators examined single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer among cases with ESCC. A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P < 10-5 in a meta-analysis of NCI and Henan GWAS data. In stage 2 with additional Henan subjects, the association for rs79747906 (18p11.31) was replicated, with a pooled odds ratio of 1.59. The findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases. (Song X, Li WQ, Hu N, et al. GWAS follow-up study of esophageal squamous cell carcinoma identifies potential genetic loci associated with family history of upper gastrointestinal cancer. Sci Rep 2017 Jul 5)

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Gallbladder

Cholangiocarcinoma Risk Factors

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare resource, investigators found that non-alcoholic fatty liver disease was associated with approximately three-fold increased risk of intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinomas. Other metabolic conditions, including obesity and type 2 diabetes, smoking, autoimmune/inflammatory conditions (type 1 diabetes and gout), viral hepatitis, alcohol-related disorders, and bile duct conditions were also associated with both cancer types. (Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based study in SEER-Medicare. PLoS One 2017)

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Genetics

Germline TP53 Variants

Li-Fraumeni syndrome is an autosomal-dominant cancer predisposition disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime; the actual population prevalence is still unclear, most likely due to biased selection of cancer-affected families. To provide population estimates, the authors analyzed the prevalence of potentially pathogenic TP53 variants in three aggregated datasets composed of 63,983 individuals unselected for personal or familial cancer history. Based on this analysis, the prevalence of potentially pathogenic TP53 exonic variants may be as high as 0.2% (range = 0.06–0.2%), up to 10 times higher than previously estimated from family-based studies. These results point to the need for further studies aimed at evaluating cancer penetrance modifiers, as well as the cancer risk associated with rare TP53 variants, to enrich knowledge of variant curation for clinical purposes. (de Andrade KC, Mirabello L, Stewart DR, et al. Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. Hum Mutat 2017; Epub Sep 21)

Skin Pigmentation

A genome-wide association study of 1570 Africans identified variants significantly associated with skin pigmentation, which clustered in four genomic regions that together account for almost 30% of the phenotypic variation. Examining ethnically diverse African genomes, variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2, and HERC2 were significantly associated with skin pigmentation. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of ultraviolet response genes under selection in Eurasians. These findings may help determine if humans with certain DNA sequences are more or less susceptible to DNA damage caused by ultraviolet radiation or respond to cellular stress differently. (Crawford NG, Kelly DE, Hansen ME, Crawford NG, et al. Loci associated with skin pigmentation identified in African populations. Science 2017; Epub Oct 12). For more information, read New Regions of the Human Genome Linked to Skin Color Variation in Some African Populations in Research News & Highlights.

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Head and Neck

Dietary Flavonoids

Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Data from the NIH-AARP Diet and Health Study showed that the highest quintile of total flavonoid intake was associated with a 24 percent lower risk of head and neck cancer compared with the lowest quintile. Notably, anthocyanidins were associated with a 28 percent lower risk of head and neck cancer and flavanones were associated with a 22 percent lower risk of head and neck cancer. No associations between flavonoid intake and risk of esophageal or gastric cancers were found. (Sun L, Subar AF, Bosire C, et al. Dietary flavonoid intake reduces the risk of head and neck but not esophageal or gastric cancer in U.S. men and women. J Nutr 2017; Epub Jul 19)

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Kidney

Telomere Length

Two investigations examined the relationship between telomere length and renal cell carcinoma (RCC). In the first, genotypes from nine telomere length-associated variants for 10,784 cases and 20,406 cancer-free controls from six genome-wide association studies of RCC were aggregated into a weighted genetic risk score predictive of leukocyte telomere length. The data suggested that individuals with inherited predisposition to longer telomeres are at increased risk of developing RCC. The second study evaluated leukocyte telomere length as a potential biomarker of survival after diagnosis of RCC. Data from 684 cases from the U.S. Kidney Cancer Study and 241 cases from the Prostate, Lung, Colon, and Ovary Screening Trial suggested that shorter leukocyte telomere length is an independent marker of poor RCC prognosis, particularly for stage-I disease. (Machiela MJ, Hofmann JN, Carreras-Torres R, et al. Genetic variants related to longer telomere length are associated with increased risk of renal cell carcinoma. Eur Urol 2017; Epub Aug 7; Callahan CL, Schwartz K, Ruterbusch JJ, et al. Leukocyte telomere length and renal cell carcinoma survival in two studies. Br J Cancer 2017; Epub Jul 25)

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Liver

Cholangiocarcinoma Risk Factors

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare resource, investigators found that non-alcoholic fatty liver disease was associated with approximately three-fold increased risk of intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinomas. Other metabolic conditions, including obesity and type 2 diabetes, smoking, autoimmune/inflammatory conditions (type 1 diabetes and gout), viral hepatitis, alcohol-related disorders, and bile duct conditions were also associated with both cancer types. (Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based study in SEER-Medicare. PLoS One 2017)

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Lung

Insulin Resistance

Investigators examined prediagnostic serum insulin, glucose, and indices of insulin resistance (insulin: glucose molar ratio and homeostasis model assessment of insulin resistance [HOMA-IR]) and lung cancer risk within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7 percent higher among a non-case subcohort than cases. Men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile (HR=2.10). A similar relationship was seen with HOMA-IR (HR=1.83). (Argirion I, Weinstein SJ, Männistö S, et al. Serum insulin, glucose, indices of insulin resistance, and risk of lung cancer. Cancer Epidemiol Biomarkers Prev 2017; Epub Jul 11)

Time to First Cigarette

Using data from the prospective National Lung Screening Trial (NLST), researchers evaluated whether adding time-to-first-cigarette (TTFC), a nicotine dependency measurement, can improve lung-cancer risk-prediction models. Smokers with TTFC≥60 minutes had much lower risk of developing or dying from lung cancer, compared to smokers with TTFC≤5 minutes. Including TTFC, a low-cost, non-invasive question, into risk models might better identify smokers with lower risk, and therefore could be a safe, convenient tool to improve identification of individuals who benefit less from lung-cancer screening. (Gu F, Cheung LC, Freedman ND, et al. Potential impact of including time-to-first-cigarette into risk models for selecting ever-smokers for lung-cancer screening. J Thorac Oncol 2017; Epub Aug 14)

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Melanoma

Germline Variants in Familial Melanoma

Known high-risk genes account for < 40% of risk for cutaneous malignant melanoma (CMM) in melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The investigators systematically characterized rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. They identified a number of rare loss-of-function variants and predicted deleterious missense variants that were enriched in CMM cases, some demonstrating co-segregation with disease within families, such as variants in TYR, PLA2G6, and ATM. Several variants also showed evidence for enrichment in population-based sporadic CMM cases. Further, compared with their corresponding controls, familial CMM cases had an increased burden of rare germline variants in TYR and OCA2, and sporadic cases had an increased burden for TYR, TYRP1, and TINF2. In particular, CMM cases seemed to have a higher frequency of rare variants in albinism-associated genes. The results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition. (Goldstein AM, Xiao Y, Sampson J, et al. Rare germline variants in known melanoma susceptibility genes in familial melanoma. Hum Mol Genet 2017; Epub Oct 3)

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Microbiome

Methods and Tool Development

In an effort to improve reproducibility in microbiome research, the authors conducted a baseline investigation of variability in taxonomic profiling for the Microbiome Quality Control (MBQC) project baseline study (MBQC-base). Blinded specimen sets from human stool, chemostats, and artificial microbial communities were sequenced by 15 laboratories and analyzed using nine bioinformatics protocols. Variability depended most on biospecimen type and origin, followed by DNA extraction, sample handling environment, and bioinformatics. Analysis of artificial community specimens revealed differences in extraction efficiency and bioinformatic classification. The results may guide researchers in experimental design choices for gut microbiome studies. (Sinha R, Abu-Ali G, Vogtmann E, et al. Assessment of variation in microbial community amplicon sequencing by the Microbiome Quality Control (MBQC) project consortium. Nat Biotechnol 2017; Epub Oct 2)

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Pancreas

Insulin-Like Growth Factors

Prediagnosis obesity and diabetes are associated with survival from pancreatic cancer, but the underlying mechanisms have not been characterized. Because both are associated with dysregulation in circulating insulin-like growth factor (IGF) levels, investigators evaluated the associations of prediagnosis IGF levels (IGF-I, IGF-II) and IGF binding protein 3 (IGFBP-3) with pancreatic cancer survival in the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial. Higher IGF-II and IGFBP-3 levels were associated with pancreatic cancer survival among men but not women. There were no statistically significant associations between IGF-I concentrations, IGF-I/IGFBP-3, and pancreatic cancer survival. (Toriola AT, Ziegler M, Li Y, et al. Prediagnosis circulating insulin-like growth factors and pancreatic cancer survival. Ann Surg Oncol 2017; Epub Jul 5)

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Physical Activity

Estrogens and Estrogen Metabolites

Researchers evaluated 15 serum estrogens and estrogen metabolites in relation to self-reported histories of physical activity and sitting among 1,804 postmenopausal women enrolled in the Women's Health Initiative Observational Study. Prolonged sitting and lower moderate- to vigorous-intensity physical activity were associated with higher levels of postmenopausal estrogens/estrogen metabolites, the estrogen metabolism patterns that have previously been associated with higher endometrial and breast cancer risk. (Oh H, Arem H, Matthews CE, et al. Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: The Women's Health Initiative Observational Study. Br J Cancer 2017; Epub Aug 17)

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Radiation

Photon Therapy

COMMENTARY: Berrington de González A, Vikram B, Buchsbaum JC, et al. A clarion call for large-scale collaborative studies of pediatric proton therapy. Int J Radiat Oncol Biol Phys 2017; Epub July 10.

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Stomach

Microbiome

Paired non-malignant and tumor tissues from gastric cancer patients from China and Mexico were used to characterize the taxonomic and derived functional profiles of gastric microbiota, and compare them with microbial profiles in other body sites using the Human Microbiome Project. Heliobacter pylori (Hp) was the most abundant member of gastric microbiota in both Chinese and Mexican samples (51 and 24 percent, respectively), followed by oral-associated bacteria. Taxonomic (phylum-level) profiles of stomach microbiota resembled oral microbiota, especially when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic sites, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. (Yu G, Torres J, Hu N, et al. Molecular characterization of the human stomach microbiota in gastric cancer patients. Front Cell Infect Microbiol 2017 Jul 6)

Nut and Peanut Butter Consumption

Data from the NIH-AARP Diet and Health Study demonstrated that both nut and peanut butter consumption were inversely associated with the risk of gastric noncardia adenocarcinoma, but had no significant association with risk of gastric cardia adenocarcinoma, esophageal adenocarcinoma, or esophageal squamous cell carcinoma. (Hashemian M, Murphy G, Etemadi A, et al. Nut and peanut butter consumption and the risk of esophageal and gastric cancer subtypes. Am J Clin Nutr 2017; Epub Aug 2)

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Thyroid

Radiation Exposure

To evaluate risk of thyroid neoplasia nearly 30 years following exposure to radioactive iodine (I-131) from the 1986 Chernobyl nuclear accident, researchers conducted a fifth cycle of thyroid screening of the Ukrainian-American cohort during 2012-2015; the first screening cycle started in 1998. A significant dose response between I-131 exposure and risk of both thyroid cancer and follicular adenoma was observed. This excess risk of malignant and benign thyroid neoplasia, which has persisted nearly three decades after exposure, underscores the importance of continued follow-up of this cohort to characterize long-term pattern of I-131 risk. (Tronko M, Brenner AV, Bogdanova T, et al. Thyroid neoplasia risk is increased nearly 30 years after the Chernobyl accident. Int J Cancer 2017; Epub Jul 10)

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Tobacco

Low-intensity Cigarette Smoking

An increasing proportion of U.S. smokers smoke ≤10 cigarettes per day (CPD) or do not smoke every day, yet the health effects of low-intensity smoking are poorly understood. Using data from the NIH-AARP Diet and Health Study, current smokers who reported consistently smoking 1-10 CPD over their lifetime were 2.3 times more likely to develop smoking-related cancer, relative to never smokers, mostly due to excess lung, bladder, and pancreatic cancer. Current lifetime smokers of <1 CPD were almost two times more likely to develop tobacco-related cancer, although the association did not reach statistical significance. Among lifelong ≤10 CPD smokers, former smokers had lower risks of smoking-related cancer with longer time since cessation. (Inoue-Choi M, Hartge P, Liao L, et al. Association between long-term low-intensity cigarette smoking and incidence of smoking-related cancer in the National Institutes of Health-AARP cohort. Int J Cancer 2017; Epub Sep 20)

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