Engels EA, Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ, Wolfe RA, Goodrich NP, Bayakly AR, Clarke CA, Copeland G, Finch JL, Fleissner ML, Goodman MT, Kahn A, Koch L, Lynch CF, Madeleine MM, Pawlish K, Rao C, Williams MA, Castenson D, Curry M, Parsons R, Fant G, Lin M.  Spectrum of cancer risk among US solid organ transplant recipients.  JAMA 2011;306:1891-1901.

Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Because most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology. The objective of this study was to describe the overall pattern of cancer following solid organ transplantation. This was a cohort study using linked data on solid organ transplant recipients from the US Scientific Registry of Transplant Recipients (1987-2008) and 13 state and regional cancer registries. Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared with the general population were the main outcome measures. The registry linkages yielded data on 175,732 solid organ transplants (58.4% for kidney, 21.6% for liver, 10.0% for heart, and 4.0% for lung). The overall cancer risk was elevated with 10,656 cases and an incidence of 1375 per 100,000 person-years (SIR, 2.10 [95% CI, 2.06-2.14]; EAR, 719.3 [95% CI, 693.3-745.6] per 100,000 person-years). Risk was increased for 32 different malignancies, some related to known infections (eg, anal cancer, Kaposi sarcoma)  and others unrelated (eg, melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (n = 1504; incidence: 194.0 per 100,000 person-years; SIR, 7.54 [95% CI, 7.17-7.93]; EAR, 168.3 [95% CI, 158.6-178.4] per 100,000 person-years) and cancers of the lung (n = 1344; incidence: 173.4 per 100,000 person-years; SIR, 1.97 [95% CI, 1.86-2.08]; EAR, 85.3 [95% CI, 76.2-94.8] per 100,000 person-years), liver (n = 930; incidence: 120.0 per 100,000 person-years; SIR, 11.56 [95% CI, 10.83-12.33]; EAR, 109.6 [95% CI, 102.0-117.6] per 100,000 person-years), and kidney (n = 752; incidence: 97.0  per 100,000 person-years; SIR, 4.65 [95% CI, 4.32-4.99]; EAR, 76.1 [95% CI, 69.3-83.3] per 100,000 person-years). Lung cancer risk was most elevated in lung  recipients (SIR, 6.13 [95% CI, 5.18-7.21]) but also increased among other recipients (kidney: SIR, 1.46 [95% CI, 1.34-1.59]; liver: SIR, 1.95 [95% CI, 1.74-2.19]; and heart: SIR, 2.67 [95% CI, 2.40-2.95]). Liver cancer risk was elevated only among liver recipients (SIR, 43.83 [95% CI, 40.90-46.91]), who manifested exceptional risk in the first 6 months (SIR, 508.97 [95% CI, 474.16-545.66]) and a 2-fold excess risk for 10 to 15 years thereafter (SIR, 2.22 [95% CI, 1.57-3.04]). Among kidney recipients, kidney cancer risk was elevated (SIR, 6.66 [95% CI, 6.12-7.23]) and bimodal in onset time. Kidney cancer risk also was increased in liver recipients (SIR, 1.80 [95% CI, 1.40-2.29]) and heart  recipients (SIR, 2.90 [95% CI, 2.32-3.59]). Compared with the general population, recipients of a kidney, liver,  heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers.

Delaney M, Warner P, Nelson K, Gleckler C, Price T, Madeleine M. Humoral immunomodulatory effect of influenza vaccine in potential blood donors: implications for transfusion safety. Transfus Med 2011;21:378-384.

Generalised immune stimulation may follow vaccination causing increased antibody titres of nonvaccine-related antibodies or bystander antibodies, including those to human leukocyte antigens (HLA) and ABO blood group antigens. HLA antibodies may lead to transfusion-related acute lung injury. High-titre ABO antibodies may cause acute haemolytic transfusion reactions after  plasma-incompatible platelet transfusion. It is unknown if these antibodies can be stimulated by vaccination in otherwise normal subjects. Blood samples of healthy volunteers who received the 2009 influenza vaccine were analysed for HLA and ABO antibodies before and 14 days after vaccination (n = 86). Age, gender and history of exposure to foreign tissue, through pregnancy, blood transfusion or tissue transplant were collected. Results were analysed with descriptive statistics, paired t-test and χ(2) test. There was no increase in HLA or ABO antibody levels after vaccination (P = not significant). Forty per cent of subjects (n = 35) had previously formed HLA antibody and 16% (7 males and 7 females) had HLA sensitisation but did not report foreign tissue exposure. The average panel reactive antibody of the HLA sensitised but nonexposed subjects was lower in males than females (3·4 and 28·6%, respectively, P = 0·015, t-test), suggesting that some females may have had unrecognised pregnancy.  HLA or ABO antibodies did not appear to be stimulated by the 2009 influenza vaccine. Female blood donors with putatively unrecognised pregnancies may have higher risk for HLA sensitisation than previously thought. Further study using different vaccine formulations may lead to better understanding of the risks of bystander antibodies in the blood donor population.

Burnett-Hartman AN, Newcomb PA, Mandelson MT, Galloway DA, Madeleine MM, Wurscher MA, Carter JJ, Makar KW, Potter JD, Schwartz SM. No evidence for human papillomavirus in the etiology of colorectal polyps. Cancer Epidemiol Biomarkers Prev 2011; 20:2288-2297.

While some studies have reported detection of oncogenic human papillomavirus (HPV) in colorectal tumors, others have not. We examined the association between oncogenic HPV infection and colorectal polyps in a case-control study of individuals with colorectal adenomas (n = 167), hyperplastic polyps (n = 87), and polyp-free controls (n = 250). We carried out real-time PCR for HPV-16 and -18 DNA, and SPF PCR covering 43 HPV types, on lesional and normal colorectal tissue samples. Plasma antibodies for oncogenic HPV types were assessed via a bead-based multiplex Luminex assay. HPV DNA was not found in any of the 609 successfully assayed colorectal  tissue samples from adenomas, hyperplastic polyps, normal biopsies adjacent to polyps, or normal biopsies of the rectum of disease-free controls. Also, there was no association between HPV seropositivity for all oncogenic HPV types combined, for either polyp type, and for men or women. When analyses were restricted to participants without a history of polyps, among men [adenomas (n =  31), hyperplastic polyps (n = 28), and controls (n = 68)], there was an association between seropositivity and hyperplastic polyps when all oncogenic HPV types were combined (OR = 3.0; 95% CI: 1.1-7.9). Overall, our findings do not support an etiologic relationship between HPV and colorectal adenomas or hyperplastic polyps; however, our finding  suggesting an association between HPV seropositivity and hyperplastic polyps in men may warrant further investigations. Impact: After stringent controls for contamination and three methods to assess HPV infection, we report no evidence for HPV in the etiology of colorectal neoplasia for either men or women.

Madeleine MM, Johnson LG, Malkki M, Resler AJ, Petersdorf EW, McKnight B, Malone KE.  Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer.  Breast Cancer Res Treat 2011; 29:887-899.

Proinflammatory cytokines are associated with age-related diseases including arthritis and heart disease. IL6 and TNF also play key roles in estrogen modulation in older women. We explored whether variation in IL6 and TNF genes influenced the risk of breast cancer in samples that differed by age group: <44 years (228 cases and 271 controls), 45-64 years (426 cases and 396 controls), and 65+ years (228 cases and 239 controls). Samples were drawn from population-based case-control studies conducted in Seattle. Age-adjusted odds ratios (ORs) were calculated to evaluate the risk associated with variants in IL6, IL6R, TNF, and TNFRSF1A. There was a significantly increased risk of breast  cancer associated with one or more C>T alleles at IL6 rs2069861 among subjects in the oldest age group (OR 1.8, 95% CI 1.1-2.9), but no overall increased risk of breast cancer associated with any IL6 or IL6R variants in the combined data. There were significantly elevated risks of breast cancer among women 45-64 years  old associated with a UTR 5' flanking SNP LTA rs2009658 C>G allele (OR 1.5, 95% CI 1.1-1.9) and a nonsynonomous coding SNP TNFRSF1A rs767455 T>C allele (OR 1.3,  95% CI 1.1-1.6); these two variants were also elevated in the combined data (OR 1.3, 95% CI 1.1-1.5 and OR 1.2, 95% CI 1.1-1.4, respectively). This study supports a modest association between a variant in IL6 and breast cancer among older women and TNF-related variants and breast cancer among middle-aged women. Further evaluation of these genes in other studies is warranted.

Guthrie KA, Gammill HS, Madeleine MM, Dugowson CE, Nelson JL.  Parity and HLA alleles in risk of rheumatoid arthritis.  Chimerism 2011; 2:11-15.

Specific HLA II alleles are associated with rheumatoid arthritis (RA) risk and others with protection. Risk-associated alleles encode similar amino acid sequences from 70 through 74 of HLA-DRβ1 (QKRAA, QRRAA, RRRAA), referred to as the "shared epitope" (SE) and protective alleles encode DERAA at the same location. Fetal-maternal cell exchange results in long-term microchimerism i.e. harboring small numbers of genetically disparate cells. Women with RA who lack the SE were recently found to harbor microchimerism with the SE more often than healthy women. This finding raises the question whether microchimerism with DERAA confers benefit against RA and is underscored by the observation that overall parity reduces RA risk. While there is currently no test for microchimerism with DERAA, we conducted studies to ask whether parity benefits women at risk for RA, either because they have the SE or lack the protective DERAA sequence. HLA genotyping was conducted for 310 RA and 571 healthy women. Parity was associated with reduced RA risk in women aged <45 years (RR 0.53, 95% CI 0.34-0.82) and further analyses examined this group. RA risk reduction with parity was greater among women with the SE than SE-negative women (RR 0.42, 95%CI 0.22-0.79 vs. RR 0.79, 0.38-1.64). Among women without DERAA, RA risk was significantly reduced with parity (RR 0.44, 95% CI 0.26-0.74) but not among DERAA-positive women (RR 0.95 95% CI 0.34-2.65). In summary, results indicate the effect of parity varied according to a woman's HLA-genotype, and women at increased risk of RA benefited most.

Johnson LG, Schwartz SM, Malkki AM, Du Q, Petersdorf EW, Galloway DA, Madeleine MM.  Risk of cervical cancer associated with allergies and polymorphisms in genes in the chromosome 5 cytokine cluster.  Cancer Epidemiol Biomarkers Prev 2011; 20:199-207.

Human papillomavirus is the acknowledged cause of cervical cancer. We hypothesized that allergies, characterized by hyperimmune reaction to common allergens andwhich have been associated with various cancers, may be related to cervical cancer, and that genetic variation in cytokine genes related to allergies might impact cervical cancer risk. We investigated the risk of invasive squamous cell cervical cancer (SCC) associated with self-reported allergies and with variation in allergy-related cytokine genes using data from a  case-control study (561 cases, 1258 controls) conducted in Washington State. Logistic regression models yielded odds ratios (OR) and 95% confidence intervals  (CI). Pollen allergy, the most commonly reported allergy, was associated with reduced SCC risk (OR 0.6, 95% CI 0.5-0.8). Of 60 tagging single nucleotide polymorphisms covering eight genes (CSF2, IL3, IL4, IL13, CSF2RB, IL4R, IL13RA1,  IL13RA2), several were related to pollen allergies among controls: IL4R rs3024647 (dominant OR 1.5 95% CI 1.0-2.3, p=0.04), CSF2RB rs16997517 (dominant OR 2.2 95%  CI 1.0-4.7, p=0.04), and IL13 rs1800925 (per-allele OR 1.7, 95% CI 1.3-2.4, p=0.0007). Two variants were inversely associated with SCC risk: IL4R rs3024656 (per-allele OR 0.8, 95% CI 0.6-1.0, p=0.03) and CSF2RB rs16997517 (dominant OR 0.4, 95% CI 0.2-0.9, p=0.04). Pollen allergies were related to reduced SCC risk. CSF2RB rs16997517 was directly related to pollen allergies in controls and to reduced SCC risk. Impact: If other studies confirm these results, the mechanism behind allergy-associated immune response associated with SCC risk  may be worth exploring in the context of therapeutic or prophylactic vaccines.