Pavel Elsakov

High incidence of 4153delA BRCA1 gene mutations in Lithuanian breast- and breast-ovarian cancer families.

SummaryBRCA1 and BRCA2 gene mutations confer a high lifetime risk to breast and ovarian cancers. We have screened cancer patients from 13 families with at least three breast and/or ovarian cancers from Lithuania for 5382insC, C61G and 4153delA BRCA1 gene mutations. One of three mutations was found in 9 of the 13 studied families (69%). 4153delA was the most frequently detected and accounted for 56% of all identified mutation. 5382insC and C61G accounted for 33% and 11% of found mutations, respectively. Significantly higher, than in other populations, incidence of 4153delA indicates that this may be founder BRCA1 mutation characteristic for Lithuanians. Our analysis shows that testing of 4153delA, 5382insC, C61G BRCA1 mutations should be extremely effective and inexpensive tool in testing Lithuanian population aimed to identify individuals with high risk of breast and ovarian cancers.

The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania.

Elsakov P, Kurtinaitis J, Petraitis S, Ostapenko V, Razumas M, Razumas T, Meskauskas R, Petrulis K, Luksite A, Lubiński J, Górski B, Narod SA, Gronwald J. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania.

Survival from Colorectal Carcinoma in HNPCC Families as Compared to the General Population in Lithuania – Initial Results

BackgroundColorectal cancer in HNPCC appears to have a better prognosis than sporadic colorectal cancer. Selection bias, screening, early intervention and treatment hamper efforts to confirm such a hypothesis.AimTo evaluate survival rates in Lithuanian HNPCC patients with colorectal cancer and compare them with survival rates of sporadic cases arising from the general population.Patients and methodsThe study group consisted of 8 patients from 6 Hereditary non-polyposis colorectal carcinoma (HNPCC) families, 3 patients had HMSH2 and 5 patients had HMLH1 mutations, who were diagnosed between 1995 and 1999. HNPCC patients characteristic (age and stage) were used to trace the records of the Cancer Registry at the same period to identify the cases corresponding the required criteria. Above 263 patients were found – 106 at stage II and 157 at stage III.ResultsThe 10-year survival was 87.5% in the HNPCC study group compared with only 44.8% in the general population group. Patients with the MSH2 gene mutation were at a greater risk of developing a second primary cancer independent from any cancer prevention and screening programs. Survival rates were also prolonged even with a greater numbers of extra-colonic cancers diagnosed at different stages.ConclusionHNPCC patients with confirmed MSH2 or MLH1 mutations diagnosed with stages II and III CRC have a good 10-year survival prognoses compared with those from the general population.

Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania

There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.

Cumulative Small Effect Genetic Markers and the Risk of Colorectal Cancer in Poland, Estonia, Lithuania, and Latvia.

The continued identification of new low-penetrance genetic variants for colorectal cancer (CRC) raises the question of their potential cumulative effect among compound carriers. We focused on 6 SNPs (rs380284, rs4464148, rs4779584, rs4939827, rs6983267, and rs10795668), already described as risk markers, and tested their possible independent and combined contribution to CRC predisposition. Material and Methods. DNA was collected and genotyped from 2330 unselected consecutive CRC cases and controls from Estonia (166 cases and controls), Latvia (81 cases and controls), Lithuania (123 cases and controls), and Poland (795 cases and controls). Results. Beyond individual effects, the analysis revealed statistically significant linear cumulative effects for these 6 markers for all samples except of the Latvian one (corrected P value = 0.018 for the Estonian, corrected P value = 0.0034 for the Lithuanian, and corrected P value = 0.0076 for the Polish sample). Conclusions. The significant linear cumulative effects demonstrated here support the idea of using sets of low-risk markers for delimiting new groups with high-risk of CRC in clinical practice that are not carriers of the usual CRC high-risk markers.

Lynch syndrome mutations shared by the Baltic States and Poland.

To the Editor : The definite diagnosis of Lynch syndrome (LS) is based on the identification of a mutation within one of the DNA mismatch repair (MMR) genes: MLH1 , MSH2 , MSH6 and PMS2 . To date, hundreds of pathogenic and suspected-pathogenic DNA variants in the MMR genes have been described worldwide (1). Large rearrangements account for about 10% of all MMR changes and can be easily detected by multiplex ligation-dependent probe amplification (MLPA), whereas substitutions, small deletions and insertions account for about 90% (2) and only full screening using either denaturing high-performance liquid chromatography (DHPLC), high resolution melting (HRM) or direct DNA sequencing seems to be the option for genetic analysis. Despite significant progress in the detection of gene mutations full screening remains expensive and time-consuming. According to the previous studies, majority of Polish families are affected by recurrent mutations found at least twice in our own series (2). That tendency provided an opportunity to design a common inexpensive assay for recurrent mutations, an approach that has been successfully applied as prescreening method (3). Founder mutations have been reported from a number of countries and geographical regions and are thought to be a result of population bottlenecks occurring throughout history. It is well recognized that populations from neighboring countries can share genetic changes and as such the probability of finding common mutation is greater. With respect to the regions bounded by Estonia, Latvia, Lithuania and Poland there are reports of common mutations occurring in these populations (4, 5).

Novel germline MSH2 mutation in lynch syndrome patient surviving multiple cancers

Lynch syndrome (LS) individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers.We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear.In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up.

Discussion on the use of taxanes for treatment of breast cancers in BRCA1 mutations carriers

BRCA1-associated cancers differ from non-hereditary cancers for many factors, including somatic mutation. It can be a subject of discussion that the natural history and response to treatment also may differ between the hereditary and sporadic subgroups. Three frequent BRCA1 mutations (5382insC, 4153delA, C61G) in the Baltic countries (Lithuania, Latvia, Byelorussia and Poland) open a way for the chip test to select a subgroup from women with breast cancer. These women with BRCA1 breast cancer have a chance to get adequate treatment, including neo-adjuvant chemotherapy. So far many retrospective studies of survival, that used the same gold standard treatment for women with BRCA1 breast cancer and for women without a mutation, have not found a difference between these groups. Some studies show a worse survival result in women with a BRCA1 mutation than women without the mutation.

Familial risk and diagnosis of colorectal cancer in young individuals

The age standardized (world) incidence (per 100000) of large bowel cancer in Lithuania is increasing: in 1993-1997 it was 25.6 for males and 16.8 for females; in 1998-2002 it was 30.4 and 19.1 respectively. Meanwhile the age standardized (world) cancer mortality remains without change: in the same periods it was 18.0 for males and 11.5 for females; 18.6 and 10.6 respectively. These epidemiological aspects are basically for start CRC screening in national population. The age for population screening recommended by EC is 50-74 years and the optimal participation rate to get better survival of CRC patients is 45-60% of population. Numerous studies have shown the risk of getting CRC is higher if a first-degree family member had the disease, and shows that your chances of surviving the disease may be influenced in part by your family ties. It hypothesized that patients with a family history of CRC might be more likely to get screened for the disease, finding tumors earlier, and are more likely to have a better prognosis. In addition to collecting family tree information help for recognition of hereditary cancer syndrome such as HNPCC, Peutz-Jeghers Polyposis, and FAP. The familial risk for CRC and effective cancer prevention become more important in individuals aged below 50-55 years. The study in Lithuania was aimed to prove more knowledge on familial CRC risk and the surveillance of family members at risk for large bowel malignancy. This study indicates that a positive family history of CRC can be recognized as a prognostic factor for individuals aged 25-39 years. Results shows that a positive family history was not a clear indicator of early stage diagnosis in the groups studied compared to the population.

Clinical genetics in cancer prevention

Cancer family history has been known to be one of the main risk factors. Members of high – risk families should be given recommendations, which may improve prophylaxis, early diagnosis and treatment. At present time is possible to identify several genes involved in the hereditary forms of some types of cancers including colorectal and breast/ovarian. Hereditary forms of breast cancer are mostly caused by mutations in such genes as BRCA1/2 and of hereditary non-polyposis colorectal cancer in genes HLMH1, HMSH2 or HMSH6. Previous studies of Lithuanian population concentrated on breast/ovarian cancer families identified three recurrent mutations 4153delA, 5382insC and C61G in BRCA1 gene. Later studies of unselected cases breast and ovarian cancer patients found that 6% of breast and 19% of ovarian cancer carried a founder mutation in the BRCA1 gene. The majority of mutation-positive patients did not have a significant family history: 71.4 % of the breast cancer patients and 87.5% of the ovarian. These and others clinical genetic aspects raise a necessity to change view on routine cancer prevention strategy, as mammography screening for breast cancer with BRCA1/2 mutations, screening by IFOBT and colonoscopy for HPCC and it is necessary to change the view on combination of chemotherapy (including neo-adjuvant) with BRCA1 positive breast cancer (anthracyclines/taxans).