A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review.

BACKGROUND: Several recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRCA1/2 genes. The aim of current study is to analyze the spectrum of the BRCA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic region. METHODS: We present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRCA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRCA1/2 using next generation sequencing (NGS). Local spectrum of the BRCA1/2 PV was compared with the Baltic region by performing a literature review. RESULTS: Founder PV c.5266dupC, c.4035delA or c.181 T > G was detected in 369/9543 (3.9%) cases. Other BRCA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRCA1 variants c.5117G > A (p.Gly1706Glu), c.4675G > A (p.Glu1559Lys), c.5503C > T (p.Arg1835*) and c.1961delA (p.Lys654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRCA1 PV and six BRCA2 PV were each found in single family. CONCLUSIONS: By combining three studies by our group of the same cohort in Latvia, frequency of the BRCA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three "historical" founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRCA1/2 sequencing. In relative numbers, c.5117G > A is currently the third most frequent PV of the BRCA1 in population of Latvia, overcoming previously known third most common founder variant c.181 T > G. In addition to three BRCA1 founder PV, a total of five recurrent BRCA1 and two recurrent BRCA2 PV have been reported in population of Latvia so far. Many of the BRCA1/2 PV reported in Latvia are shared among other populations of the Baltic region.

High frequency of pathogenic non-founder germline mutations in BRCA1 and BRCA2 in families with breast and ovarian cancer in a founder population.

BACKGROUND: Pathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population. METHODS: Fifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations. RESULTS: In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations. CONCLUSION: A relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.

The CHEK2 del5395 is a founder mutation without direct effects for cancer risk in the latvian population.

Our objective was to determine: 1) whether the checkpoint kinase 2 (CHEK2) del5395 (g.27417113-27422508 del, NC_000022.11) is a founder mutation in the Latvian population, 2) if there is an association between CHEK2 del5395 mutation and cancer risk, and 3) and whether the CHEK2 del5395 mutation impacts cancer predisposition in Chernobyl disaster liquidators (the civil and military personnel who were called upon to deal with consequences of the 1986 nuclear disaster) as well as geriatric populations. We recruited 438 breast cancer patients, 568 colorectal cancer patients, 399 ovarian cancer patients, 419 prostate cancer patients, 526 healthy blood donors, 480 Chernobyl disaster liquidators and 444 geriatric cancer-free participants. DNA samples were isolated from blood samples and subjected to multiplex polymerase chain reaction (PCR). The truncation of del5395 was estimated by fragment size of the multiplex PCR.All groups were compared to the healthy blood donors using Fisher's exact test. All p values were two-sided and the odds ratios (OR) calculated by two-by-two table. In cancer groups, the del5395 mutation was most frequently observed in the ovarian cancer group (1.00%, OR = 1.32). In control groups, the del5395 mutation was most frequent (0.76%) in the healthy donors, which exceeded its frequency in the Chernobyl liquidators group and the geriatric group by 0.01 and 0.08%, respectively. For all groups, the OR appeared to be >1 only in ovarian cancer patients. However, OR rates showed no statistical significance in either cancer or control groups, with the p value fluctuating within the range of 0.39-1.00. The CHEK2 gene del5395 is a founder mutation in the Latvian population, which, however, does not have a direct impact on genetic predisposition toward colorectal, breast, ovarian and prostate cancer.

Novel germline MLH1 and MSH2 mutations in Latvian Lynch syndrome families.

BACKGROUND/AIMS: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. METHODOLOGY: High risk colorectal cancer families were selected from overall 1053 consecutive patients. Screening of germline mutations in the MLH1 and MSH2 was performed by direct sequencing and multiplex ligation-dependent probe amplification. RESULTS: Ten patients fulfilled the Amsterdam I/II criteria and Bethesda guidelines of the Lynch syndrome. Three novel mutations were identified in MLH1 and MSH2 genes, as well as two known mutations in the MLH1 gene. Large rearrangements in the MLH1 gene were found in two patients. CONCLUSIONS: The mutations in the MLH1 and MSH2 genes in Latvian high-risk families are highly heterogeneous. Combination of direct sequencing and MLPA is the most appropriate molecular method of detecting hereditary nonpolyposis colorectal cancer patients and family members at risk.

[Severe acute pancreatitis: role for laparoscopic surgery]. / Die Rolle der laparoskopischen Chirurgie bei schwerer akuter Pankreatitis.

UNLABELLED: Minimally invasive surgery is a new and promising treatment modality in the management of patients with severe acute pancreatitis (SAP). Aim of our study was the evaluation of our first experiences with laparoscopic surgery in the management of patients with SAP. METHODS: A total of 65 patients complied with Atlanta recommendations for SAP and were included into this retrospective study. Indications for laparoscopic surgery were SAP presented with intraabdominal or retroperitoneal exudates and detected by ultrasound (US) and/or contrast enhanced computer tomography (CT) scan, and the presence of acute calculous cholecystitis when 3 to 5 days of conservative treatment did not show clinical improvement and surgical treatment was considered. Patients with improvement after initial therapy received conservative therapy only. Bacteriological cultures were done for abdominal exudates and necrotic tissue obtained during surgery. RESULTS: Totally, 39 patients were operated and 26 were treated conservatively only. Laparoscopic surgery was started in 31 patients and completed in 26 patients. The overall conversion rate was 16.1 %. Laparoscopic drainage of the intraabdominal exudate was done in 26 patients including drainage of the lesser sac in five of them. Laparoscopic cholecystectomy in 25 cases and laparoscopically assisted jejunostomy in 6 cases were performed as a part of the procedure. Conventional surgery was the primary procedure in 8 patients. Peripancreatic abscess formation was observed in one case one month after laparoscopic procedure and was cured with conventional surgical drainage. Bile leakage from the cystic stump was successfully treated with endoscopic papillotomy in one case. All patients survived after laparoscopic procedures. Overall complication rate was 7.7 % and mortality reached 3.1 %. CONCLUSIONS: Laparoscopic drainage of the abdominal cavity, drainage of the lesser sac and revision of the retroperitoneal compartment can be safely carried out as an alternative to the conventional surgical approach. Laparoscopic cholecystectomy and/or jejunostomy may be additionally performed if indicated.