Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.

Polymorphisms in nucleotide excision repair genes and susceptibility to colorectal cancer in the Polish population.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may be associated with a change in DNA repair capacity, which could be associated with colorectal cancer development. We assessed the association between 94 single nucleotide polymorphisms (SNPs) within seven XP genes (XPA-XPG) and the colorectal cancer risk in the Polish population. We genotyped 758 unselected patients with colorectal cancer and 1,841 healthy adults. We found that a significantly decreased risk of colorectal cancer was associated with XPC polymorphism rs2228000_CT genotype (OR 0.59; p < 0.0001) and the rs2228000_TT genotype (OR 0.29; p < 0.0001) compared to the reference genotype (CC). And an increased disease risk was associated with the XPD SNP, rs1799793_AG genotype (OR 1.44, p = 0.018) and rs1799793_AA genotype (OR 3.31, p < 0.0001) compared to the reference genotype. Haplotype analysis within XPC, XPD and XPG revealed haplotypes associated with an altered colorectal cancer risk. Stratified analysis by gender showed differences between the association of three SNPs: XPC rs2228000, XPD rs1799793 and XPD rs238406 in females and males. Association analysis between age of disease onset and polymorphisms in XPD (rs1799793) and XPC (rs2228000) revealed differences in the prevalence of these variants in patients under and over 50 years of age. Our results confirmed that polymorphisms in XPC and XPD may be associated with the risk of colorectal cancer.

Selenium as a marker of cancer risk and of selection for control examinations in surveillance.

Publication is summarization of existing data being results of literature review and our experience on usefulness of selenium as a diagnostic marker selection for control examinations in surveillance and as a marker of patients with high risk of cancers.

Serum Levels of Copper and Zinc and Survival in Breast Cancer Patients.

There is emerging interest in the relationship between several serum micronutrients and the prognosis of patients with breast cancer. The relationship between serum zinc and copper levels and breast cancer prognosis is unclear. In our study, we included 583 patients with breast cancer diagnosed between 2008 and 2015 in the region of Szczecin, Poland. In a blood sample obtained before treatment, serum zinc and copper levels were quantified by mass spectroscopy. Each patient was assigned to one of four categories (quartiles) based on the distribution of the elements in the entire cohort. Patients were followed from diagnosis to death over a mean of 10.0 years. The 10-year overall survival was 58.3% for women in the highest and 82.1% for those in the lowest quartile of serum copper/zinc ratio (p < 0.001). The multivariate hazard ratio (HR) for breast cancer death was 2.07 (95% CI 1.17-3.63; p = 0.01) for patients in the highest quartile of serum copper/zinc ratio compared to those in the lowest. There is evidence that the serum zinc level and copper/zinc ratio provide an independent predictive value for overall survival and breast cancer-specific survival after breast cancer diagnosis.

Can selenium levels act as a marker of colorectal cancer risk?

BACKGROUND: Selenium has attracted attention because of its antioxidant properties. Antioxidants protects cells from damage. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing the immune cell activity and suppressing the development of tumor blood vessels. In this observational study, selenium level was measured in a series of patients from Poland and Estonia to determine a correlation between levels of this microelement and colorectal cancer risk. METHODS: A total of 169 colorectal cancer patients and 169 healthy controls were enrolled in the study after obtaining their informed consent. Selenium level in the blood serum was measured using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). The statistical analysis was performed by Fisher's exact test. RESULTS: The threshold point of selenium level was 55 µg/l and 65 µg/l for Poland and Estonia respectively, for an increase in cancer risk. The lower levels of selenium were associated with greater risk of colorectal cancer. CONCLUSIONS: The result reveals a significant strong association between low selenium level and the colorectal cancer risk in both Estonian and Polish populations.

Factors determining the quality of life in patients undergoing radical surgery due to malignant tumors of the rectum.

INTRODUCTION: Rectal cancer is one of the most common malignancies in developed countries. However, despite the increasingly better preoperative diagnostics, adaptation of surgical techniques to the location and advancement of the tumor, the combination of surgical treatment with neoadjuvant therapy and adjuvant treatment, standardized control tests, Poland still has not obtained satisfactory results regarding long-term survival. In addition, the effects of the therapy often differ significantly from those expected by patients and the doctors treating them. AIM OF THE STUDY: To evaluate the effects of rectal cancer treatment among patients of the General and Oncological Surgery Clinic of the Pomeranian Medical University in Szczecin. The impact of numerous factors on postoperative quality of life was analyzed. MATERIAL AND METHODS: Between 2007 - 2015, 263 radical resection procedures were performed in patients with diagnosed rectal cancer. Retrospectively, based on medical records, a database was created covering a range of clinical data. Information about death dates of some patients was obtained at the Registry Office in Szczecin. A survey supplementing clinical data and standardized quality of life assessment forms (EORTC QLQ - C30 and CR29) were sent to 120 living patients. A telephone conversation was carried out with some patients who did not respond to the surveys. Finally, data from 90 people was collected, which represents 75% of the patients enrolled in the study. Patients quality of life was assessed using EORTC questionnaire evaluation guides. RESULTS: The patients quality of life worsened the most as a result of anorectal dysfunction. Incontinence of gases and stool, urgency and difficulty in defecation were demonstrated primarily in patients undergoing low rectal resection and irradiation. Patients undergoing radiotherapy, as a result of persistent low anterior resection syndrome, were forced to partially or completely withdraw from professional activity and to limit the pursuit of their interests. Their contacts with family, friends and acquaintances have also deteriorated. The presence of the intestinal stoma significantly affected the deterioration of the reception of the body's own image. However, no relation was found between the existence of the fistula and other aspects of the patients everyday life, including functioning in life and social roles. CONCLUSIONS: Due to the acceptable postoperative quality of life of patients with fistula and numerous imperfections of sphincter preserving techniques, operations resulting in terminal ostomy should not be considered as an extremity, and in the case of tumors of the lower rectum with unaffected sphincters, they should be considered as alternative methods for low anterior resection.

Colorectal cancer and Blastocystis sp. infection.

BACKGROUND: Blastocystis sp. is a common intestinal protozoan found worldwide. Based on gene analysis, 17 subtypes (STs, ST1-ST17) have been identified, 9 of which have been isolated from humans. Differences in clinical consequences may depend on differences among the STs. Here, we evaluated the prevalence of Blastocystis sp. in patients with colorectal cancer (CRC) compared to a control group and assessed the relationships between Blastocystis sp. infection and sex; age; and CRC grade, stage, and location. METHODS: The study included 107 CRC patients (41 women and 66 men, median age 65 years); 124 subjects without colorectal cancer or a history of oncological disease comprised the control group (55 women and 69 men, median age 63). Stool samples were collected from patients before oncological treatment and examined using light microscopy (iodine-stained smear). Additionally, PCR-based identification of Blastocystis sp. was performed in 95 stool samples from CRC patients and 76 stool samples from the control group. RESULTS: Light microscopy showed that the prevalence of Blastocystis sp. was significantly higher in CRC patients than in the control group (12.15% and 2.42%, respectively; p = 0.0041). Multivariate analysis showed that the odds of Blastocystis sp. infection were fivefold higher in the CRC group than in the control group. PCR-based molecular examinations demonstrated that the proportion of patients infected with Blastocystis sp. was significantly higher in the CRC group than in the control group (12.63% and 2.63%, respectively; p = 0.023). The predominant ST in the CRC group was ST3, detected in nine patients (75%), followed by ST1 (2 patients, 16.7%) and ST2 (1 patient, 8.3%). No association was found between Blastocystis sp. infection and age, sex, or CRC stage, grade, or location. CONCLUSIONS: The results showed that CRC was associated with an increased risk of opportunistic Blastocystis sp. infection, even before oncological treatment. To the best of our knowledge, this is the first report estimating the prevalence of Blastocystis sp. infection in CRC patients before oncological treatment in Europe.

Leiomyosarcoma in adrenal gland.

Not required for Clinical Vignette.

Blood Copper Levels and the Occurrence of Colorectal Cancer in Poland.

There is a need for sensitive and specific biomarkers for the early detection of colorectal cancer. In this retrospective study, we assessed whether a high blood copper level was associated with the presence of colorectal cancer. The blood copper level was measured among 187 colorectal cancer patients and 187 matched controls. Cases and controls were matched for sex, smoking status (yes/no) and year of birth. Among the cases, the mean blood copper level was 1031 µg/L (range 657 µg/L to 2043 µg/L) and among the controls, the mean blood copper level was 864 µg/L (range 589 µg/L to 1433 µg/L). The odds ratio for colorectal cancer for those in the highest quartile of copper level (versus the lowest) was 12.7 (95% CI: 4.98-32.3; p < 0.001). Of the patients with stage I-II colon cancer, 62% had a copper level in the highest quartile. A blood copper level in excess of 930 µg/L is associated with an increase in the prevalence of colorectal cancer in the Polish population and its potential use in early detection programs should be considered.

Low Blood-As Levels and Selected Genotypes Appears to Be Promising Biomarkers for Occurrence of Colorectal Cancer in Women.

In following study we examined whether blood arsenic (As) levels combined with specific polymorphisms in MT1B, GSTP1, ABCB1, NQO1, CRTC3, GPX1, SOD2, CAT, XRCC1, ERCC2 can be used as a marker for the detection of colorectal cancer (CRC) among Polish women. A retrospective case-control study of CRC included 83 CRC cases and 78 healthy controls. From each study participant pre-treatment peripheral blood was collected for As level measurement by inductively coupled-plasma mass spectrometry (ICP-MS). We estimated the odds ratio (OR) of the association between blood-As levels and CRC using multivariable unconditional logistic regression models. A low blood-As level (0.27-0.67 µg/L) was associated with an increased frequency of CRC (OR: 3.69; p = 0.005). This correlation was significantly greater when participants carried particular gene variants: CAT, rs1001179-nonCC (OR: 19.4; p = 0.001); ABCB1 rs2032582-CC (OR: 14.8; p = 0.024); GPX1 rs1050450-CC (OR: 11.6; p = 0.002) and CRTC3 rs12915189-nonGG (OR: 10.3; p = 0.003). Our study provides strong evidence that low blood-As levels are significantly associated with increased CRC occurrence and that particular gene variants significantly enhanced this correlation however, due to the novelty of these findings, we suggest further validation before a definitive statement that the combined effect of low blood-As levels with specific gene polymorphisms is a suitable CRC biomarker.

Serum Selenium Level Predicts 10-Year Survival after Breast Cancer.

In a recent prospective study, we reported an association between a low serum selenium level and five-year survival among breast cancer patients. We now have updated the cohort to include 10-year survival rates. A blood sample was obtained from 538 women diagnosed with first primary invasive breast cancer between 2008 and 2015 in the region of Szczecin, Poland. Blood was collected before initiation of treatment. Serum selenium levels were quantified by mass spectroscopy. Each patient was assigned to one of four quartiles based on the distribution of serum selenium levels in the whole cohort. Patients were followed from diagnosis until death or last known alive (mean follow-up 7.9 years). The 10-year actuarial cumulative survival was 65.1% for women in the lowest quartile of serum selenium, compared to 86.7% for women in the highest quartile (p < 0.001 for difference). Further studies are needed to confirm the protective effect of selenium on breast cancer survival. If confirmed this may lead to an investigation of selenium supplementation on survival of breast cancer patients.

CHEK2 mutations and HNPCC-related colorectal cancer.

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty-five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR-positive families). A positive association between the CHEK2 I157T mutation and HNPCC-related cancer was observed only for MMR-negative cases (OR = 2.1; p = 0.0004), but not for MMR-positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR-negative cases with familial colorectal cancer (2 or more first-degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR-negative, HNPCC/HNPCC-related families in Poland.

Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility.

BACKGROUND: CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. METHODS: We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. RESULTS: The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. CONCLUSION: Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

Genetic contribution to all cancers: the first demonstration using the model of breast cancers from Poland stratified by age at diagnosis and tumour pathology.

The aim of the study is to verify the hypothesis that genetic polymorphisms are associated with the predisposition to all malignancies. Using as a model breast cancers from the homogenous Polish population (West Pomeranian region) after stratification of 977 patients by age at diagnosis (under 51 years and above 50 years) and by tumour pathology (ductal cancers--low and high grade, lobular cancers, ER-positive/negative) we tested this hypothesis. Altogether 20 different groups of breast cancer cases have been analyzed. The results were compared to a group of unaffected controls that were matched by age, sex, ethnicity and geographical location and originated from families without cancers of any site among relatives. Molecular alterations selected for analyses included those which have been previously recognized as being associated with breast cancer predisposition. Statistically significant differences between the breast cancer cases and controls were observed in 19 of the 20 analyzed groups. Genetic changes were present in more than 90% of the breast cancer patients in 18 of 20 groups. The highest proportion of cases with constitutional changes-99.3% (139/140) was observed for lobular cancers. The number and type of genetic marker and/or the level of their association with the specific cancer predisposition was different between groups. Markers associated with majority of groups included: BRCA1, CHEK2, p53, TNRnTT, FGFRnAA, XPD CC/AA and XPD GG. Some markers appeared to be group specific and included polymorphisms in CDKN2A, CYP1B1, M3K nAA, and RS67.

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk.

BACKGROUND: Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers. METHODS: In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFalpha) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls). RESULTS: Of the six genes only one polymorphism in TNFalpha(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFalpha -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFalpha -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs). CONCLUSION: The association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.

5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients.

DPYD gene encodes dihydropyrimidine dehydrogenase which is the initial and rate-limiting enzyme in the metabolism of 5-fluorouracil (5-FU). The aim of our study was PCR-RFLP based-genetic testing for the most common 5-FU toxicity-attributable IVS14 + 1G > A DPYD mutation (DPYD(*)2A) in 252 Polish colorectal cancer (CRC) patients treated with this adjuvant chemotherapeutic regimen after surgery. The DPYD(*)2A allele was identified only in one patient: a male who was one of 4 CRC patients suffering from grades 3-4 myelotoxicity upon 5-FU chemotherapy. We conclude that IVS14 + 1G > A DPYD (DPYD(*)2A) variant occurs in the Polish population and is responsible for a significant proportion of life-threatening toxicity of 5-FU.

Colorectal cancer and Cryptosporidium spp. infection.

Transient or constant impaired immunity is often associated with neoplastic disease or oncological treatment. Among the most common pathogens found in patients with HIV or patients undergoing chemotherapy are protozoans of the Cryptosporidium genus, which cause diarrhea in humans and animals. The present study determined the frequency of Cryptosporidium spp. infections in patients with colorectal cancer (N = 108; 42 women; 66 men; median age, 65 years), before beginning oncological treatment, compared to a control group (N = 125; 56 women, 69 men; median age, 63 years) without colorectal cancer or a history of oncological disease. We also assessed whether Cryptosporidium spp. infections were associated with age, gender, cancer stage (based on Astler-Coller or TNM classification), histological grade, or cancer location. Patients were treated at the Pomeranian Medical University, in 2009-2014. The presence of Cryptosporidium spp. antigen was determined in stool samples, analyzed with a commercial immunoenzymatic test. Cryptosporidium spp. infections occurred significantly more often (p = 0.015) in patients (13%) compared to controls (4%). The patient group showed no significant relationship between Cryptosporidium spp. infection and sex, age, tumor location, cancer grade, or stage. A multivariate logistic regression analysis adjusted for age and sex that included all subjects (patient + control groups, n = 233) showed that the odds of a Cryptosporidium spp. infection were more than three-fold higher in patients than in controls, and more than six-fold higher among men than among women. CONCLUSIONS: 1) Cryptosporidium spp. infections occurred significantly more frequently in patients with colorectal cancer (before oncological treatment) compared to controls, independent of age and sex. 2) Cryptosporidium spp. infections were not associated with the colorectal cancer stage, grade, or location or with patient age. 3) Male gender was significantly related to the frequency of Cryptosporidium spp. infections, independent of age and the presence of colorectal cancer.

Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?

Germline mutations in cell cycle checkpoint kinase 2 (CHEK2) have been associated with a range of cancer types, in particular of the breast and prostate. Protein-truncating mutations in CHEK2 have been reported to confer higher risks of cancer of the breast and the prostate than the missense I157T variant. In order to estimate the risks of colorectal cancer associated with truncating and missense CHEK2 mutations, we genotyped 1085 unselected colorectal cancer cases and 5496 controls for four CHEK2 founder mutations present in Poland. We observed an increased risk of colorectal cancer in association with the missense I157T mutation (odds ratios (OR) = 1.5; 95% CI 1.2-2.0; P = 0.002) but not with truncating mutations (OR = 1.0; 95% CI 0.5-1.8; P = 0.9); however the difference in the two OR was not statistically significant (P = 0.2). We conclude that the I157T mutation increases the risk of colorectal cancer in the population, but that truncating mutations may confer a lower risk or no increase in risk. It is important that other studies of CHEK2 mutation carriers be conducted to confirm this hypothesis.

Epistatic relationship between the cancer susceptibility genes CHEK2 and p27.

We studied the effects of p27 and CHEK2 variants on prostate and colon cancer risk in a case-control study. Modest effects on prostate cancer risk were observed for both CHEK2 missense and truncating variants. However, the excess cancer risk was restricted to the subgroup of men who were homozygous for the VV genotype in codon 109 of the p27 gene. Among men with the VV p27 genotype, the odds ratios associated with truncating and missense CHEK2 mutations were 3.1 (P < 0.0001) and 1.9 (P < 0.0001), respectively. Among men with other p27 genotypes (GG and VG), the odds ratios were 1.5 and 1.2 for truncating and missense CHEK2 mutations, respectively, and were not statistically significant. The interaction between CHEK2 and p27 was confirmed in a group of patients with colon cancer. Thus, it seems that the clinical expression of CHEK2 variant alleles on prostate and colon cancer risk may be restricted to individuals with a specific genotype (VV) of the p27 gene. Two-gene models provide numerous challenges for gene identification and cancer risk assessment.