Whole-exome sequencing identifies a novel germline variant in PTK7 gene in familial colorectal cancer

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC

Risk of Second Primary Thyroid Cancer in Women with Breast Cancer

The goal of this study was to estimate the risk of thyroid cancer following breast cancer and to identify therapeutic and genetic risk factors for the development of thyroid cancer after breast cancer. We followed 10,832 breast cancer patients for a mean of 14 years for new cases of thyroid cancer. All women were genotyped for three Polish founder mutations in BRCA1 (C61G, 4153delA, 5382insC) and four mutations in CHEK2 (1100delC, IVS2 + 1G/A, del5395, I157T). Information was collected on chemotherapy, radiotherapy, hormonal therapies, and oophorectomy. Of the 10,832 women, 53 (0.49%) developed a second primary thyroid cancer. Based on Polish population statistics, the expected number was 12.4 (SIR = 4.3). The ten-year risk of developing thyroid cancer was higher in women who carried a CHEK2 mutation (1.5%) than in women who carried no mutation (0.9%). The age-adjusted hazard ratio for developing thyroid cancer was 1.89 (0.46–7.79; p = 0.38) for those with a CHEK2 protein-truncating mutation and 2.75 (1.29–5.85; p = 0.009) for those with a CHEK2 missense mutation

Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study

The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated so far. Herein, we examined the possible association of E318K and a novel variant of the MITF gene, V320I, with the risk of cancers of different sites of origin in a Polish population. We assayed for the presence of the E318K and V320I missense mutations in 4,226 patients with one of six various cancers (melanoma or cancer of the kidney, lung, prostate, colon, or breast) and 2,114 controls from Poland. The E318K mutation was detected in 4 of 2,114 participants (0.19%) in the Polish control population, the V320I in 3 of 2,114 participants (0.14%) in the control group. We found no statistically significant differences in the prevalence of the E318K and V320I variants among cases and controls. We found two carriers of the E318K variant among melanoma patients (P = 0.95), one carrier among breast cancer patients (P = 0.77), one carrier among colorectal cancer patients (P = 0.82), and one carrier among kidney cancer patients (P = 0.64). Our study demonstrates a lack of strong association of E318K and V320I with increased risk of melanoma or cancers of the kidney, breast, prostate, lung, or colon

Genetic predisposition to male breast cancer in Poland

Abstract Background Breast cancer in men accounts for fewer than 1 % of all breast cancer cases diagnosed in men and women. Genes which predispose to male breast cancer include BRCA1 and BRCA2. The role of other genes is less clear. In Poland, 20 founder mutations in BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL are responsible for the majority of hereditary breast cancer cases in women, but the utility this genes panel has not been tested in men. Methods We estimated the prevalence of 20 alleles in six genes (BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL) in 165 Polish male breast cancer patients. We compared the frequency of selected variants in male breast cancer cases and controls. Results One of the 20 mutations was seen in 22 of 165 cases (13.3%). Only one BRCA1 mutation and two BRCA2 mutations were found. We observed statistically significant associations for PALB2 and CHEK2 truncating mutations. A PALB2 mutation was detected in four cases (OR = 11.66; p < 0.001). A CHEK2 truncating mutation was detected in five cases (OR = 2.93;p = 0.02). Conclusion In conclusion, we recommend that a molecular test for BRCA1, BRCA2, PALB2 and CHEK2 recurrent mutations should be offered to male breast cancer patients in Poland

Prevalence of Recurrent Mutations Predisposing to Breast Cancer in Early-Onset Breast Cancer Patients from Poland

There are twenty recurrent mutations in six breast-cancer-predisposing genes in Poland (BRCA1, BRCA2, CHEK2, PALB2, NBN, and RECQL). The frequencies of the twenty alleles have not been measured in a large series of early-onset breast cancer patients from Poland unselected for family history. We genotyped 2464 women with breast cancer diagnosed below age 41 years for twenty recurrent germline mutations in six genes, including BRCA1, BRCA2 CHEK2, PALB2, NBN, and RECQL. A mutation in one of the six genes was identified in 419 of the 2464 early-onset breast cancer cases (17%), including 22.4% of those cases diagnosed below age 31. The mutation frequency was 18.8% for familial breast cancer cases and 6% for non-familial cases. Among women with breast cancer below age 31, the mutation frequency was 23.6% for familial cases and 17.4% in non-familial cases. The majority of mutations (76.2%) were seen in BRCA1 and BRCA2. In Poland, a panel of twenty recurrent mutations in six genes can identify a genetic basis for a high percentage of early-onset cases and testing is recommended for all women with breast cancer at age 40 or below