First description of mutational analysis of <Emphasis Type="Italic">MLH1, MSH2</Emphasis> and <Emphasis Type="Italic">MSH6</Emphasis> in Algerian families with suspected Lynch syndrome

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand-dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families.     

Loss of MSH2 and MSH6 due to heterozygous germline defects in <Emphasis Type="Italic">MSH3</Emphasis> and <Emphasis Type="Italic">MSH6</Emphasis>

Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hits in both genes abrogate all binding partners for the MSH2 protein which might subsequently be degraded. The clinical relevance of MSH3 germline variants is currently under re-evaluation, and heterozygous MSH3 defects alone do not seem to induce a LS phenotype, but might aggravate the MSH6 phenotype in affected family members.     

<Emphasis Type="Italic">PALB2</Emphasis> analysis in <Emphasis Type="Italic">BRCA2</Emphasis>-like families

BRCA2 and PALB2 function together in the Fanconi anemia (FA)–Breast Cancer (BRCA) pathway. Mono-allelic and bi-allelic BRCA2 and PALB2 mutation carriers share many clinical characteristics. Mono-allelic germline mutations of BRCA2 and PALB2 are risk alleles of female breast cancer and have also been reported in familial pancreatic cancer, and bi-allelic mutations cause a severe form of Fanconi anemia. In view of these similarities, we investigated whether the prevalence of PALB2 mutations was increased in breast cancer families with the occurrence of BRCA2 associated tumours other than female breast cancer. PALB2 mutation analysis was performed in 110 non-BRCA1/2 cancer patients: (a) 53 ovarian cancer patients from female breast-and/or ovarian cancer families; (b) 45 breast cancer patients with a first or second degree relative with pancreatic cancer; and (c) 12 male breast cancer patients from female breast cancer families. One truncating PALB2 mutation, c.509_510delGA, resulting in p.Arg170X, was found in a male breast cancer patient. We conclude that germline mutations of PALB2 do not significantly contribute to cancer risk in non-BRCA1/2 cancer families with at least one patient with ovarian cancer, male breast cancer, and/or pancreatic cancer.     

Screening for exonic copy number mutations at <Emphasis Type="Italic">MSH2</Emphasis> and <Emphasis Type="Italic">MLH1</Emphasis> by MAPH

Background: Exonic deletions in MSH2 and MLH1 are significant contributors to the mutation spectrum in HNPCC, and heterozygous changes in exon copy number are not detected by conventional mutation screening methods. Aims: We aimed to develop methods for screening copy number changes in all the exons of the MLH1 and MSH2 genes using a single multiplex amplifiable probe hybridisation (MAPH) assay. Methods: We developed a probe set consisting of probes from the 19 exons of MLH1 and 16 exons of MSH2, and 3 control probes, and applied it to screening for deletions and duplications using fluorescent detection of amplified fragments. Results: We tested 73 DNA samples from controls and 50 from HNPCC patients in whom no point mutations had been found, and detected 10 copy number changes among the patient samples. A deletion of about 1.4 kb including exon 3 of MSH2 was confirmed by amplification of a junction fragment, and was shown to be the result of an unequal recombination between intronic Alu elements. Conclusions: MAPH can detect exonic copy number changes in MLH1 and MSH2 in DNA from HNPCC patients. Since finding an exonic deletion or duplication makes full sequence analysis unnecessary, it may be most cost-effective to pre-screen samples by MAPH or MLPA before screening for point mutations.     

Prevalence of <Emphasis Type="Italic">BRCA2</Emphasis> and <Emphasis Type="Italic">CDKN2a</Emphasis> mutations in German familial pancreatic cancer families

Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer. As the prevalence of those mutations in the setting of familial pancreatic cancer is still not well defined for the German population, we evaluated the presence of BRCA2 and CDKN2a germline mutations in a large cohort of familial pancreatic cancer (FPC) families from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Fifty-six FPC families with at least two-first-degree relatives with confirmed pancreatic cancer that did not fulfill the criteria of other tumor predisposition syndromes, were analyzed for BRCA2 and CDKN2a germline mutations by DHPLC and/or direct sequencing. No deleterious CDKN2a mutations were identified in our families suggesting that CDKN2a mutations are unlikely to predispose PC in FPC families without melanoma. No deleterious BRCA2 mutations, but 6 unclassified variants, were detected in our FPC collection. Combining the prevalence of deleterious BRCA2 germline mutations from our previous separate study with the data from this study we were able to much more accurately estimate the BRCA2 carrier frequency for FPC families in the German population. A total of two mutations and 6 unclassified variants (mutation range: 2.8–11.4%) were thus identified in 70 German FPC families, indicating that the prevalence of BRCA2 mutations in the German FPC population is less frequent than previously reported.     

Managing Patient with Mutations in <Emphasis Type="Italic">PALB2</Emphasis>, <Emphasis Type="Italic">CHEK2</Emphasis>, or <Emphasis Type="Italic">ATM</Emphasis>

Purpose of Review

The use of panel testing of multiple cancer-causing genes has allowed to find a subset of patients with harmful mutations in moderate penetrance genes. While extensive information is available regarding patients with BRCA1 and BRCA2 pathogenic variants, information regarding these less common genes and their management remains scarce. The aim of this review is to discuss penetrance, incidence, and management recommendations for PALB2, ATM, and CHEK2.

Recent Findings

NCCN guidelines now provide management recommendation for patients with pathogenic variants in these genes. In addition, more widespread testing has provided more information on penetrance and incidence. Although this is a huge step toward improving quality of care, prospective studies are still needed. We summarize the NCCN and other guidelines/suggestions for these genes and deliver our insight on the matter based on the best information we could find.

Summary

PALB2, ATM, and CHEK2 are less penetrant than BRCA1–2 and have a different spectrum, suggesting differing management. Data about incidence and penetrance along with management recommendations for these genes are provided.

     

Selection of patients with germline <Emphasis Type="Italic">MLH1</Emphasis> mutated Lynch syndrome by determination of <Emphasis Type="Italic">MLH1</Emphasis> methylation and <Emphasis Type="Italic">BRAF</Emphasis> mutation

Lynch syndrome is one of the most common hereditary colorectal cancer (CRC) syndrome and is caused by germline mutations of MLH1, MSH2 and more rarely MSH6, PMS2, MLH3 genes. Whereas the absence of MSH2 protein is predictive of Lynch syndrome, it is not the case for the absence of MLH1 protein. The purpose of this study was to develop a sensitive and cost effective algorithm to select Lynch syndrome cases among patients with MLH1 immunohistochemical silencing. Eleven sporadic CRC and 16 Lynch syndrome cases with MLH1 protein abnormalities were selected. The BRAF c.1799T> A mutation (p.Val600Glu) was analyzed by direct sequencing after PCR amplification of exon 15. Methylation of MLH1 promoter was determined by Methylation-Sensitive Single-Strand Conformation Analysis. In patients with Lynch syndrome, there was no BRAF mutation and only one case showed MLH1 methylation (6%). In sporadic CRC, all cases were MLH1 methylated (100%) and 8 out of 11 cases carried the above BRAF mutation (73%) whereas only 3 cases were BRAF wild type (27%). We propose the following algorithm: (1) no further molecular analysis should be performed for CRC exhibiting MLH1 methylation and BRAF mutation, and these cases should be considered as sporadic CRC; (2) CRC with unmethylated MLH1 and negative for BRAF mutation should be considered as Lynch syndrome; and (3) only a small fraction of CRC with MLH1 promoter methylation but negative for BRAF mutation should be true Lynch syndrome patients. These potentially Lynch syndrome patients should be offered genetic counselling before searching for MLH1 gene mutations.     

The yield of targeted genotyping for the recurring mutations in <Emphasis Type="Italic">BRCA1</Emphasis>/<Emphasis Type="Italic">2</Emphasis> in Israel

Background

Hereditary breast cancer is predominantly associated with germline mutations in the BRCA1 or BRCA2 genes. A few recurring mutations in these genes were reported in ethnically diverse Jewish populations. Since 2013, most oncogenetic laboratories in Israel adopted a two-step approach for BRCA1/2 genotyping, where the first step is genotyping for 14 seemingly recurring mutations—first-pass genotyping. The aim of this study was to assess the yield of this targeted BRCA sequencing.

Methods

Clinical and genotyping data of all individuals who underwent oncogenetic counseling and first-pass BRCA genotyping at the Oncogenetic Service Sheba and Assaf Harofeh Medical Centers from 1 February 2013 to 30 June 2017 were reviewed. All study participants were unrelated to each other.

Results

Overall, 5152 oncogenetic tests were reviewed in the present study, of which 4452 had no a priori known familial mutation. The majority of participants (68.6%) were genotyped because of personal history of cancer; 20.6% were tested because of family history of cancer, and details for the remaining 10.7% were missing. Overall, 256/4452 (5.8%) carriers were detected, 141 BRCA1 and 115 BRCA2 mutation carriers. In 54% of cancer-free carriers, no clinically suspicious family history of cancer was ascertained.

Conclusions

The currently used scheme of first-pass genotyping in Israel seems to have a high yield of mutation detection even in the absence of a significant family history of cancer. The challenge is to optimize the currently used targeted panel of common mutations and adjust it to the accumulating new data in the Israeli population.

     

Higher occurrence of childhood cancer in families with germline mutations in <Emphasis Type="Italic">BRCA2</Emphasis>, MMR and <Emphasis Type="Italic">CDKN2A</Emphasis> genes

The contribution of hereditary factors for development of childhood tumors is limited to some few known syndromes associated with predominance of tumors in childhood. Occurrence of childhood tumors in hereditary cancer syndromes such as BRCA1/2 associated breast and ovarian cancer, DNA-mismatch repair (MMR) genes associated hereditary non polyposis colorectal cancer and CDKN2A associated familial malignant melanoma are very little studied. Herein we report the prevalence of childhood tumors (diagnosed ≤18 years of age) in families identified with mutation in the BRCA1/2, MMR and CDKN2A genes. Using pedigrees at the Regional Oncogenetic Clinic at Lund University Hospital, the prevalence of childhood cancer was estimated in families with mutations in the BRCA1 (n = 98), BRCA2 (n = 43) MMR (MLH1, MSH2 MSH6) (n = 31) and CDKN2A (n = 15) genes in comparison with population based control families (n = 854). Compared with the control group, a significantly higher prevalence of childhood cancer was found in families with mutations in BRCA2 (9.3% vs. 0.8% P = 0.001), MMR genes (19.4% vs. 0.8% P < 0.001) and CDKN2A (20.0% vs. 0.8% P < 0.001), but not in families with BRCA1 mutations (1.0% vs. 0.8% P = 0.6). Further analyses showed an increased risk for childhood tumors in families with mutations in BRCA2 (OR 12.4; 95% CI 3.5–44.1), MMR genes (OR 29.0; 95% CI 9.1–92.6), and CDKN2A (OR 30.2; 95% CI 7.0–131.1). This study suggests that the risk for childhood tumors is increased in families with germline mutations in the BRCA2, MMR and CDKN2A genes.     

Prognostic significance of co-overexpression of the <Emphasis Type="Italic">EGFR</Emphasis>/<Emphasis Type="Italic">IGFBP-2</Emphasis>/<Emphasis Type="Italic">HIF-2A</Emphasis> genes in astrocytomas

Overexpression of the EGFR, IGFBP-2 and HIF-2A genes has been observed in high-grade astrocytomas and these genes seem to be functionally related to one another. This study aimed to define the profile of their expressions, interactions and correlation with clinical features and prognostic significance in microdissected tumor samples from 84 patients with astrocytomas of different grades and from 6 white matter non-neoplasic brain tissue sample. EGFR, IGFBP-2 and HIF-2A gene expression levels were analyzed by quantitative real-time PCR and differed significantly between grades I–IV astrocytic tumors (P < 0.0001, P < 0.0001 and P: 0.0013, respectively) when analyzed by the Kruskal–Wallis test. Grade I astrocytomas presented gene expression levels similar to those encountered in samples of microdissected white matter of non-neoplastic brain tissue Overexpression of the EGFR, IGFBP-2 and HIF-2A genes was significantly associated with lower 2-year survival (P: 0.009, P: 0.0002 and P: 0.008, respectively). Co-overexpression of these genes was strongly associated with high-grade gliomas and lower survival in univariate (P < 0.0001) and multivariate (P: 0.009) analysis, suggesting that the co-expression of the EGFR/IGFBP-2/HIF-2A pathway genes may have a more important clinical and biological impact than the expression of each individual gene alone. These data support the existence of a common pathway involving these genes that could contribute to the design of new target treatments.     

Induction of apoptosis by <Emphasis Type="Italic">p53</Emphasis>, <Emphasis Type="Italic">bax</Emphasis>, <Emphasis Type="Italic">bcl-2</Emphasis>, and <Emphasis Type="Italic">p21</Emphasis> expressed in colorectal cancer

Background We investigated the influence of genes on the apoptosis of colorectal tumor cells, based on DNA and mRNA kinetics.Methods In 30 colorectal cancer patients, we examined the mRNA expression of p53, bax, bcl-2, and p21 ^WAF1 , and we also investigated the development of tumor cell apoptosis, using a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method.Results TUNEL-positive cells showed a positive correlation with bax (P = 0.010) and a negative correlation with p21 (P = 0.04). We also investigated the relationship between p53 point mutation, p21 immunostaining degree, and apoptosis, based on DNA ladder expression. A remarkable correlation (P = 0.0090) was found between p21 and apoptosis.Conclusions The present study findings suggest that tumor cell apoptosis is (1) strongly inhibited by p21, (2) induced by bax, and (3) influenced by bcl-2, which, presumably, inhibits tumor cell apoptosis.     

Immunohistochemical null-phenotype for mismatch repair proteins in colonic carcinoma associated with concurrent <Emphasis Type="Italic">MLH1</Emphasis> hypermethylation and <Emphasis Type="Italic">MSH2</Emphasis> somatic mutations

Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual “null” IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient’s age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.     

Cancer risk management in Tasmanian women with <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations

Women carrying germline mutations in BRCA1 or BRCA2 have significantly increased lifetime risks of breast and tubo-ovarian cancer. To manage the breast cancer risk women may elect to have breast screening by MRI/mammogram from age 30, to take risk-reducing medication, or to have a prophylactic bilateral mastectomy. To manage the tubo-ovarian cancer risk, the only effective strategy is to have a bilateral salpingo-oophorectomy, recommended by age 40 (BRCA1) or ‘around’ age 40 (BRCA2). Early studies suggested that uptake of these cancer risk-reducing strategies was low. More recent studies have revealed higher rates of uptake, however it is unclear whether uptake is genuinely improving or whether the higher uptake rates reflect changes in the populations studied. In this study we surveyed 193 BRCA1/2 mutation carriers in the state of Tasmania to determine the uptake of cancer risk-reducing strategies and what factors might influence women’s decisions in relation to both gynaecological and breast surgery. We observed that uptake of risk management strategies varied depending on the strength of the recommendation in the national guidelines. Uptake rates were >?90% for strategies which are strongly recommended, such as breast screening by MRI/mammogram and bilateral salpingo-oophorectomy, and were unaffected by demographic factors such as socio-economic disadvantage and educational achievement. Uptake rates were much lower for strategies which are presented in the guidelines as options for consideration and where patient choice and shared decision making are encouraged, such as prophylactic mastectomy (29%) and chemoprevention (1%) and in the case of prophylactic mastectomy, were influenced by both socio-economic advantage and educational achievement.     

Sporadic endometrial adenocarcinoma with MMR deficiency due to biallelic <Emphasis Type="Italic">MSH2</Emphasis> somatic mutations

The invalidation of the Mismatch Repair (MMR) system is responsible for a so-called “deficient MMR” phenotype (dMMR) characterized by microsatellite instability and abnormal pattern of expression of MMR proteins in tumor tissue. This phenotype occurs in at least 20% of sporadic endometrial adenocarcinomas by epigenetic silencing of MLH1 gene. It is also observed in virtually all tumors occurring in patients with Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR—pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR—pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome. We report the case of a woman with an early-onset endometrial adenocarcinoma who was suspected to be affected with Lynch syndrome based on tumor dMMR phenotype (MSI associated with loss of expression of MSH2 and MSH6 proteins). After complete germline and somatic evaluations, this phenotype was eventually explained by two MSH2 somatic mutations and the diagnosis of Lynch-like syndrome due to an unidentified MSH2 germline mutation was ruled out. Somatic mosaicism at low mutation rate was unlikely as no mutation was detected by DNA analysis from various tissue samples. Nevertheless, the three patient’s children were tested for the two mutations and these tests were negative. Biallelic somatic mutations of one MMR gene is a mechanism of invalidation of the MMR system in sporadic cases. Clinicians have to be aware of this mechanism because of the great clinical implication for the patients and their relatives.     

Recurrent <Emphasis Type="Italic">APC</Emphasis> gene mutations in Polish FAP families

The molecular diagnostics of genetically conditioned disorders is based on the identification of the mutations in the predisposing genes. Hereditary cancer disorders of the gastrointestinal tracts are caused by mutations of the tumour suppressor genes or the DNA repair genes. Occurrence of recurrent mutation allows improvement of molecular diagnostics. The mutation spectrum in the genes causing hereditary forms of colorectal cancers in the Polish population was previously described. In the present work an estimation of the frequency of the recurrent mutations of the APC gene was performed. Eight types of mutations occurred in 19.4% of our FAP families and these constitute 43% of all Polish diagnosed families.     

<Emphasis Type="Italic">BRAF</Emphasis>/K-<Emphasis Type="Italic">ras</Emphasis> mutation,microsatellite instability,and promoter hypermethylation of <Emphasis Type="Italic">hMLH1</Emphasis>/<Emphasis Type="Italic">MGMT</Emphasis> in human gastric carcinomas

Background The BRAF and K-ras genes are the most frequently mutated oncogenes in various human malignancies. We examined BRAF and K-ras mutations in human gastric cancer, and investigated their relationship with microsatellite instability (MSI) and the hypermethylation of promoter regions in hMLH1 and O ⁶ -methylguanine DNA methyltransferase (MGMT).Methods Sixteen gastric cancer cell lines and 62 gastric cancer tissue samples were screened for BRAF and K-ras mutations by direct sequencing. We also performed a microsatellite assay and investigated methylation status in the promoter regions of hMLH1 and MGMT.Results mutation was not found in any of the cancer cell lines examined. One (1.6%) cancer tissue sample showed a point mutation in the BRAF gene (GT_G GA_G; V599E). K-ras mutation (GG_T GA_T, G12D) was detected in five (31%) gastric cancer cell lines and in 1 (1.6%) gastric cancer tissue sample. In the gastric cancer tissue samples examined, MSI was detected in 23 (37%) samples. Hypermethylated promoter regions in hMLH1 and MGMT, respectively, were detected in 6 (10%) and 13 (21%) gastric cancer tissue samples. Microsatellite stable (MSS) tumors showed frequent lymphatic invasion (P = 0.050).Conclusion Although BRAF mutation has been reported in a variety of other human cancers, it is a rare event in the carcinogenesis and progression/development of gastric cancer.     

Mutation analysis of <Emphasis Type="Italic">PALB2</Emphasis> in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>-negative breast and/or ovarian cancer families from Eastern Ontario,Canada

Background

PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.

Methods

The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.

Results

We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.

Conclusions

PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.     

<Emphasis Type="Italic">ABI3</Emphasis> ectopic expression reduces <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>cell growth properties while inducing senescence

Background  

Mounting evidence has indicated that ABI3 (ABI family member 3) function as a tumor suppressor gene, although the molecular mechanism by which ABI3 acts remains largely unknown.     

Double germline mutations in <Emphasis Type="Italic">APC</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> in an individual with a pancreatic tumor

We report on three brothers affected by pancreatic tumors, all due to different causes, including mutations associated with two different cancer predisposition syndromes in the same individual. In the index patient a germline mutation both in the APC and BRCA2 gene was identified while one affected brother showed the BRCA2 mutation only and another brother is supposed to have developed pancreatic cancer due to multiple non-genetic risk factors. We outline the impact of a double germline mutation in two tumor predisposition genes in one individual and proven heterogeneity of multiple cases of pancreatic tumors in one family. With the growing implementation of next generation sequence based panel testing for multiple genes involved in tumor predisposition syndromes, relevant variants in two (or more) genes will be found more frequently. This family illustrates the importance of family studies, especially when using gene panel tests.