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Purpose: To characterize the spectrum of BRCA1 and BRCA2 pathogenic germline variants in women from south-west Poland and west Ukraine affected with breast or ovarian cancer. Testing in women at high risk of breast and ovarian cancer in these regions is currently mainly limited to founder mutations., Methods: Unrelated women affected with breast and/or ovarian cancer from Poland (n = 337) and Ukraine (n = 123) were screened by targeted sequencing. Excluded from targeted sequencing were 34 Polish women who had previously been identified as carrying a founder mutation in BRCA1. No prior testing had been conducted among the Ukrainian women. Thus, this study screened BRCA1 and BRCA2 in the germline DNA of 426 women in total., Results: We identified 31 and 18 women as carriers of pathogenic/likely pathogenic (P/LP) genetic variants in BRCA1 and BRCA2, respectively. We observed five BRCA1 and eight BRCA2 P/LP variants (13/337, 3.9%) in the Polish women. Combined with the 34/337 (10.1%) founder variants identified prior to this study, the overall P/LP variant frequency in the Polish women was thus 14% (47/337). Among the Ukrainian women, 16/123 (13%) women were identified as carrying a founder mutation and 20/123 (16.3%) were found to carry non-founder P/LP variants (10 in BRCA1 and 10 in BRCA2)., Conclusions: These results indicate that genetic testing in women at high risk of breast and ovarian cancer in Poland and Ukraine should not be limited to founder mutations. Extended testing will enhance risk stratification and management for these women and their families.

Protein tyrosine phosphatase receptor type J (PTPRJ, DEP1) is a tumour suppressor gene that negatively regulates such processes as angiogenesis, cell proliferation and migration and is one of the genes important for tumour development. Similar to other phosphatase genes, PTPRJ is also described as an oncogene. Among various genetic changes characteristic for this gene, single nucleotide polymorphisms (SNPs) constituting benign genetic variants that can modulate its function have been described. We focused on Gln276Pro and Arg326Gln missense polymorphisms and performed a meta-analysis using data from 2930 and 852 patients for Gln276Pro and Arg326Gln respectively in different cancers. A meta-analysis was performed based on five articles accessed via the PubMed and Research Gate databases. Our meta-analysis revealed that for Arg326Gln, the presence of the Arg (C) allele was associated with lower risk of some cancers, the strongest association was observed for colorectal cancer patients, and there was no association between Gln276Pro (G>T) polymorphism and cancer risk. The polymorphisms Arg326Gln and Gln276Pro of the PTPRJ gene are not associated with an increased risk of cancer except for the Arg326Gln polymorphism in colorectal cancer. Large-scale studies should be performed to verify the impact of this SNP on individual susceptibility to colorectal cancer for given individuals.

Background: FANCM and RECQL have recently been reported as breast cancer susceptibility genes and it has been suggested that they should be included on gene panel tests for breast cancer predisposition. However, the clinical value of testing for mutations in RECQL and FANCM remains to be determined. In this study, we have characterised the spectrum of FANCM and RECQL mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine., Methods: We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of FANCM and RECQL in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease., Results: Among 427 women screened, we identified one carrier of the FANCM:c.1972C > T nonsense mutation (0.23%), and two carriers of the frameshift insertion FANCM:c.1491dup (0.47%). None of the variants we observed in RECQL were predicted to be loss-of-function mutations by standard variant effect prediction tools., Conclusions: Our study of the Polish and Ukrainian populations has identified a carrier frequency of truncating mutations in FANCM consistent with previous reports. Although initial reports suggesting that mutations in RECQL could be associated with increased breast cancer risk included women from Poland and identified the RECQL:c.1667_1667 + 3delAGTA mutation in 0.23-0.35% of breast cancer cases, we did not observe any carriers in our study cohort. Continued screening, both in research and diagnostic settings, will enable the accumulation of data that is needed to establish the clinical utility of including RECQL and FANCM on gene panel tests.

Aim: Colorectal cancer (CRC) is one of the most common cancers worldwide and, although the majority of cases are sporadic, its development and progression depends on a range of factors: environmental, genetic and epigenetic. A variety of genetic pathways have been described as being crucial in CRC, including protein tyrosine phosphatases (PTPs). PTPN13 (also called FAP-1) is a non-receptor PTP and interacts with a number of important components of growth and apoptosis pathways. It is also involved in the inhibition of Fas-induced apoptosis., Method: The single nucleotide polymorphism genotype at Y2081D (T>G) (rs989902) of PTPN13 exon 39 was determined in DNA extracted from blood samples from 174 sporadic CRC patients and 176 healthy individuals. Also, a meta-analysis was performed based on three articles accessed via the PubMed and ResearchGate databases., Results: The risk of CRC was 2.087 times greater for patients with the GG genotype than for those with the TT genotype (P = 0.0475). In the meta-analysis, a significantly increased risk of cancer associated with the G allele was observed in the squamous cell carcinoma of the head and neck subgroup (TT vs GG+GT, OR 1.23, 95% CI [1.02, 1.47], P = 0.0258), and a significantly decreased risk in the breast cancer subgroup (TT vs GG+GT, OR 0.63, 95% CI [0.41, 0.96], P = 0.0334) and in the CRC subgroup (GT+TT vs GG, OR 0.51, 95% CI [0.41, 0.95], P = 0.0333)., Conclusion: PTPN13 rs989902 is significantly associated with the risk of CRC in the Polish population. Given that this report provides the first evidence of an association of PTPN13 rs989902 with the risk of CRC in a Caucasian population, further large scale studies are necessary to confirm this finding., (Colorectal Disease © 2017 The Association of Coloproctology of Great Britain and Ireland.)

The protective effect of vitamin D against several cancers including colorectal cancer is modulated by the vitamin D receptor (VDR) and its ligand, the active form of vitamin D. VDR response has been found to play a role in various genes encoding proteins involved in crucial cellular pathways. Single nucleotide polymorphisms (SNPs) of the VDR gene that modulate its activity are located in the promoter region, exons 2-9, and their vicinity and also in the 3'UTR region. Some of them have been previously studied in relation to cancer susceptibility and prognosis. The aim of our study was to investigate four polymorphisms, BsmI, ApaI, TaqI, and FokI, of the VDR gene in Polish patients with sporadic colorectal cancer and to evaluate their association with susceptibility to cancer. We found a significant association between the BsmI genotype and cancer (individuals with the bb genotype are more susceptible to cancer compared to those with other genotypes, p = 0.025, Fisher's exact test for 2 × 2 table). Also, the TT genotype at TaqI and the AA genotype at ApaI are correlated with a higher risk of cancer (p = 0.00071 and p = 1.0 × 10(-5), respectively). We found relatively strong linkage disequilibrium between the TaqI and ApaI loci (T with A and t with a, respectively). Both of these loci are associated with cancer. We do not observe any such association for the FokI polymorphism. In conclusion, a small modification in VDR expression may play a role in such a multipathway process as tumorigenesis.

Epidemiological data show that colorectal cancer (CRC) is the second most frequent malignancy worldwide. The involvement of "minor impact genes" such as XME and DNA-repair genes in the etiology of sporadic cancer has been postulated by other authors. We focused on analyzing polymorphisms in DNA-repair genes in CRC. We considered the following genes involved in DNA-repair pathways: base excision repair (OGG1 Ser326Cys, XRCC1 Trp194Arg and Arg399Gln); nucleotide excision repair [XPA (-4)G/A, XPC C/A (i11) and A33512C (Lys939Gln), XPD Asp312Asn and A18911C (Lys751Gln), XPF Arg415Gln, XPG Asp1104His, ERCC1 C118T]; homologous recombination repair [NBS1 Glu185Gln, Rad51 135G/C, XRCC3 C18067 (Thr241Met)]. The study group consisted of 133 patients diagnosed with sporadic CRC, while the control group was composed of 100 age-matched non-cancer volunteers. Genotyping was performed by PCR and PCR-RFLP. Fisher's exact test with a Bonferroni correction for multiple testing was used. We found that: (i) XPC C/A (i11) heterozygous variant is associated with increased risk of CRC [OR is 2.07 (95% CI 1.1391, 3.7782) P=0.038], (ii) XPD A18911C (Lys751Gln) is associated with decreased risk of CRC [OR=0.4497, (95% CI 0.2215, 0.9131) P=0.031] for an individual with at least one A allele at this locus. (1) The XPC C/A (i11) genotype is associated with an increased risk of sporadic colorectal cancer. (2) The NER pathway has been highlighted in our study, as a most important in modulation of individual susceptibility to sCRC.