Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10-29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10-63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10-5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Vaccination History and Risk of Lymphoma and Its Major Subtypes.

BACKGROUND: Vaccinations have been hypothesized to play a role in lymphoma etiology, but there are few studies, mixed results, and limited data on lymphoma subtypes. Herein, we investigate the association of vaccinations with risk of major lymphoma subtypes. METHODS: We studied 2,461 lymphoma cases and 2,253 controls enrolled from 2002 to 2014. Participants self-reported history of vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza. Polytomous logistic regression was used to estimate OR and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS: After multivariable adjustment, vaccination against influenza was inversely associated with lymphoma (OR = 0.82; 95% CI, 0.66-1.02), which was stronger for last vaccination 1+ years before enrollment (OR = 0.71; 95% CI, 0.56-0.91) and for >5 influenza vaccinations (OR = 0.56; 95% CI, 0.46-0.68). Ever vaccination against hepatitis A (OR = 0.81; 95% CI, 0.66-1.00) but not hepatitis B (OR = 0.97; 95% CI, 0.81-1.18) was associated with lymphoma risk, although more recent vaccinations were inversely associated with lymphoma risk for both hepatitis A (<6 years before enrollment, OR = 0.56; 95% CI, 0.40-0.77) and hepatitis B (<9 years before enrollment, OR = 0.72; 95% CI, 0.55-0.93). Ever vaccination against yellow fever was inversely associated with risk (OR = 0.73; 95% CI, 0.55-0.96), and this did not vary by time since last vaccination. Although there was no overall statistical evidence for heterogeneity of vaccination history by lymphoma subtype, the only statistically significant inverse associations were observed for influenza and yellow fever vaccinations with diffuse large B-cell and follicular lymphoma. CONCLUSIONS: Selected vaccinations were inversely associated with lymphoma risk, with time since last vaccination relevant for some of these vaccines. IMPACT: Vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza are unlikely to increase lymphoma risk.

Body mass index and survival of patients with lymphoma.

The impact of body mass index (BMI) on survival in lymphoma remains controversial. We leveraged a prospective cohort of lymphoma patients enrolled to SPORE Molecular Epidemiology Resource between 2002 and 2015 to assess the association of BMI before diagnosis, BMI at diagnosis, and BMI change over time with lymphoma-specific survival (LSS). A total of 4009 lymphoma patients (670 diffuse large B-cell lymphoma (DLBCL), 689 follicular lymphoma (FL), 1018 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and 1632 other subtypes) were included. Significantly shorter LSS after diagnosis was observed for FL patients who were obese before diagnosis (HR: 3.02, 95%CI: 1.43-6.41, p=.004) and for those with a ≥ 5% increase in BMI from diagnosis to 3-year follow-up (HR: 3.53, 95%CI: 1.22-10.2, p=.020). In contrast, obesity prior to or at the time of diagnosis was not associated with LSS in DLBCL and CLL/SLL. The impact of weight control after diagnosis in FL patient warrants investigation.

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case-control study.

Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). We evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In our American-based Mayo Clinic case-control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144-item food frequency questionnaire. Logistic regression-calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association (trend p-value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]) was as follows: meat replacement (0.67 [0.43-1.02]), total protein (0.58 [0.39-0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated FAs (0.64 [0.42, 0.98]) and linoleic acid (FA 18:2) (0.62 [0.40-0.95]). Increased risk associations were observed for saturated FAs (1.48 [0.97-2.23]), butyric acid (FA 4:0) (1.77 [1.19-2.64]), caproic acid (FA 6:0) (2.15 [1.42-3.27]), caprylic acid (FA 8:0) (1.87 [1.27-2.76]) and capric acid (FA 10:0) (1.83 [1.23-2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose-dependent manner, whereas fats found in dairy increase risk.

Polymorphisms in metabolism/antioxidant genes may mediate the effect of dietary intake on pancreatic cancer risk.

OBJECTIVES: A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. METHODS: A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls' median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. RESULTS: Significant increased associations (Bonferroni corrected P ≤ 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, α; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50-4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. CONCLUSIONS: Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.

Meat-related mutagens and pancreatic cancer: null results from a clinic-based case-control study.

BACKGROUND: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design. METHODS: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. RESULTS: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. CONCLUSIONS: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. IMPACT: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat.

Nutrients from fruit and vegetable consumption reduce the risk of pancreatic cancer.

PURPOSE: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. Our objective was to evaluate the risk of pancreatic cancer associated with nutrients found in fruits and vegetables and nutrient supplementation using a clinic-based case-control design. METHODS: Our study included 384 rapidly ascertained cases and 983 controls frequency-matched on age at time of recruitment (in 5-year increments), race, sex, and region of residence. All subjects provided demographic information and completed a 144-item food frequency questionnaire in which they reported no change to their diet within 5 years prior to entering the study. Logistic regression was used to calculate odds ratios and 95 % confidence intervals, adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. RESULTS: Results show a significant (trend p value < 0.05) inverse association between pancreatic cancer and nutrient/supplement groupings in a dose-dependent manner including magnesium, potassium, selenium, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, niacin, total alpha-tocopherol, total vitamin A activity, vitamin B6, and vitamin C. Adjusting for diabetes or total sugar intake did not result in significant changes. CONCLUSION: We conclude that most nutrients obtained through consumption of fruits and vegetables may reduce the risk of developing pancreatic cancer.

Fruit and vegetable consumption is inversely associated with having pancreatic cancer.

OBJECTIVE: Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case-control study specifically designed to address limitations of both cohort and case-control studies to examine the relationship. METHODS: Participants were excluded who reported changing their diet within 5 years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (±5 years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. RESULTS: Comparing highest to lowest quintiles, we observed significant inverse associations (OR < 0.8) with significant trends (p (trend) < 0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake. CONCLUSIONS: We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies.

Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.