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Picelli S.,Karolinska Institutet | Zajac P.,KTH Royal Institute of Technology | Zhou X.-L.,Karolinska Institutet | Edler D.,Karolinska University Hospital | And 15 more authors.
European Journal of Cancer | Year: 2010

The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR = 1.52; CI = 1.06-2.17). When the analysis was restricted to our 'super-controls', healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI = 1.02-1.60) and 1.34 (CI = 1.05-1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI = 0.60-0.97) among colon patients and 0.73 (CI = 0.56-0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles. © 2010 Elsevier Ltd. All rights reserved.

Karlsson M.,Karolinska Institutet | Marits P.,Karolinska Institutet | Dahl K.,South Stockholm General Hospital | Dagoo T.,South Stockholm General Hospital | And 3 more authors.
Annals of Surgical Oncology | Year: 2010

Background. Despite optimal surgical treatment and modern adjuvant therapies, 50% of patients diagnosed with colorectal cancer die within 5 years. Immunotherapy offers an appealing complement to traditional chemotherapy, with possible long-term protection against tumor recurrences through immunological memory. We have conducted a pilot study of a novel adoptive immunotherapy, using autologous, in vitro expanded lymphocytes isolated from the tumor-draining sentinel lymph node. Study Design. Sentinel nodes were recovered from 16 patients with disseminated or locally advanced, high-risk colorectal cancer. Single-cell suspensions of sentinel-nodeacquired lymphocytes were clonally expanded in vitro in the presence of autologous tumor extract and returned as a transfusion. Patients were followed with clinical and radiological evaluations. Long-term survival was compared with traditionally treated controls. Results. Sentinel-node-acquired CD4+ Th1-lymphocytes could be clonally expanded in vitro and safely administered to all 16 patients without side-effects. In four out of nine stage IV patients, complete tumor regression occurred. Median survival time in the stage IV patients (n = 9) was 2.6 years, as compared with 0.8 years in conventionally treated controls. A dose-dependent effect with regards to reduced tumor burden and long-term survival was observed. Conclusion. Sentinel-node-based adoptive immunotherapy is feasible; the method has shown no apparent sideeffects and appears to convey therapeutic antitumor effects. Further studies are justified to determine its efficacy and precise role in the treatment of colorectal cancer. © The Author(s) 2010.

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