BRCA1 – Conductor of the Breast Stem Cell Orchestra: The Role of BRCA1 in Mammary Gland Development and Identification of Cell of Origin of BRCA1 Mutant Breast Cancer

Breast cancer treatment has been increasingly successful over the last 20 years due in large part to targeted therapies directed against different subtypes. However, basal-like breast cancers still represent a considerable challenge to clinicians and scientists alike since the pathogenesis underlying the disease and the target cell for transformation of this subtype is still undetermined. The considerable similarities between basal-like and BRCA1 mutant breast cancers led to the hypothesis that these cancers arise from transformation of a basal cell within the normal breast epithelium through BRCA1 dysfunction. Recently, however, a number of studies have called this hypothesis into question. This review summarises the initial findings which implicated the basal cell as the cell of origin of BRCA1 related basal-like breast cancers, as well as the more recent data which identifies the luminal progenitor cells as the likely target of transformation. We compare a number of key studies in this area and identify the differences that could explain some of the contradictory findings. In addition, we highlight the role of BRCA1 in breast cell differentiation and lineage determination by reviewing recent findings in the field and our own observations suggesting a role for BRCA1 in stem cell regulation through activation of the p63 and Notch pathways. We hope that through an increased understanding of the BRCA1 role in breast differentiation and the identification of the cell(s) of origin we can improve treatment options for both BRCA1 mutant and basal-like breast cancer subgroups.     

Systematic biochemical analysis of somatic missense mutations in DNA polymerase β found in prostate cancer reveal alteration of enzymatic function

DNA polymerase β is essential for short-patch base excision repair. We have previously identified 20 somatic pol β mutations in prostate tumors, many of them missense. In the current article we describe the effect of all of these somatic missense pol β mutations (p.K27N, p.E123K, p.E232K, p.P242R, p.E216K, p.M236L, and the triple mutant p.P261L/T292A/I298T) on the biochemical properties of the polymerase in vitro, following bacterial expression and purification of the respective enzymatic variants. We report that all missense somatic pol β mutations significantly affect enzyme function. Two of the pol β variants reduce catalytic efficiency, while the remaining five missense mutations alter the fidelity of DNA synthesis. Thus, we conclude that a significant proportion (9 out of 26; 35%) of prostate cancer patients have functionally important somatic mutations of pol β. Many of these missense mutations are clonal in the tumors, and/or are associated with loss of heterozygosity and microsatellite instability. These results suggest that interfering with normal polymerase β function may be a frequent mechanism of prostate tumor progression. Furthermore, the availability of detailed structural information for pol β allows understanding of the potential mechanistic effects of these mutants on polymerase function.     

Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome

Alstr?m syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alstr?m syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease.     

Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families?

Panchal S, Bordeleau L, Poll A, Llacuachaqui M, Shachar O, Ainsworth P, Armel S, Eisen A, Sun P, Narod SA. Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families? Women who carry BRCA mutations are advised to begin breast cancer screening based on the age‐specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario‐based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.     

Genome exploration of six variants of the Ostreid Herpesvirus 1 and characterization of large deletion in OsHV-1μVar specimens

The genetic polymorphism of the Ostreid Herpesvirus 1 (OsHV-1) has generally been investigated in three areas: ORFs 4/5, ORFs 42/43, and ORFs 35 to 38. The present study, however, focuses on 40 ORFs, representing 30% of the OsHV-1 genome, encoding four categories of putative proteins: 4 ORFs encoding putative inhibitor of apoptosis proteins; 17 ORFs encoding membrane proteins; 10 ORFs encoding secreted proteins; and 9 ORFs encoding RING finger proteins. The potential role of these proteins in major steps of the life cycle of the OsHV-1 motivated their selection. Seven specimens have been selected in accordance with their nucleotide variations in the C region (area located between the end of the ORF4 and the beginning of ORF 5): 3 OsHV-1 μVar specimens, 2 OsHV-1 μVar Δ9, one specimen of OsHV-1 μVar Δ15, and one OsHV-1 specimen (reference control) close to the reference genome to validate PCRs. The OsHV-1 μVar is mainly characterized by a deletion of 12 consecutive nucleotides followed by a deletion of one adenine in a microsatellite area located in the C region. A representation of nucleotide modifications between the different specimens was performed by building evolutionary trees with respect to the category of ORFs. This phylogenetic analysis revealed two groups: the first one corresponded to the reference control and the reference genome AY509253, and the second one included the 6 OsHV-1 variants. These results suggest that the two main groups come from the same common ancestor, and that the divergence between the reference OsHV-1 and its variants occurred quite far back in time. Moreover, consequences of nucleotide variations in the amino acid sequences, especially the change of the N glycoslyation sites, were investigated. Herein is the first report of four important deletions in these OsHV-1 μVar variants: a deletion of 1385 bp in ORF 11; a deletion of 599 bp in ORF 48; a deletion of 3549 bp in ORFs 61 to 64; and a deletion of 712 bp in ORF 114. The size of the deletions differed between OsHV-1 μVar specimens, OsHV-1 μVar Δ9 specimens, and the OsHV-1 μVar Δ15 specimen. These zones seem to correspond to special points of gene rearrangements for producing new proteins. Further investigation necessary proves to link such nucleotide modifications with consequences of protein functions in the OsHV-1 life cycle.     

Medical Mistrust Influences Black Women’s Level of Engagement in BRCA1/2 Genetic Counseling and Testing

Clinical evidence supports the value of BRCA1/2 genetic counseling and testing for managing hereditary breast and ovarian cancer risk; however, BRCA1/2 genetic counseling and testing are underutilized among black women, and reasons for low use remain elusive. We examined the potential influence of sociocultural factors (medical mistrust, concerns about genetic discrimination) on genetic counseling and testing engagement in a sample of 100 black women at increased risk for carrying a BRCA1/2 mutation. Eligible participants fell into 1 of 3 groups: (1) healthy women with at least 1 first-degree relative affected by breast and/or ovarian cancer, (2) women diagnosed with breast cancer at age less than or equal to 50 years, and (3) women diagnosed with breast and/or ovarian cancer at age greater than or equal to 50 years with either 1 first-degree relative or 2 second-degree relatives with breast and/or ovarian cancer. Participants were recruited from clinical and community settings and completed a semistructured interview. Study variable relationships were examined using bivariate tests and multivariate regression analysis. As expected, genetic counseling and testing engagement among this sample was low (28%). After accounting for sociodemographic factors and self-efficacy (β = 0.37, p < .001), women with higher medical mistrust had lower genetic counseling and testing engagement (β = -0.26, p < .01). Community-level and individual interventions are needed to improve utilization of genetic counseling and testing among underserved women. Along with trust building between patients and providers, strategies should enhance women’s personal confidence. The impact of medical mistrust on the realization of the benefits of personalized medicine in minority populations should be further examined in future studies.     

Study of genetic heterogeneity of hemoglobinopathy and β-thalassemia molecular variants in newborns

A complex of molecular-genetic and biochemical methods, such as hemoglobin isoelectric focusing and the amplification of refractory mutation systems, have been used for the first time to screen for inherited hemoglobinopathies among newborns in Baku. The phenotypical frequencies of pathological genes of α- and β-thalassemias and abnormal hemoglobins S and D were 2.48, 1.95, 0.35, and 0.09%, respectively. Three types of mutations at β-thalassemia were identified, including the deletion of two nucleotides (two adenines) in codon 8 of the first exon (36.2%), the substitution of the guanine nucleotide for the adenine nucleotide at position 110 of intron-1, and the substitution of guanine nucleotide for adenine nucleotide at position 1 of intron-2 (13.79%) in the β-hemoglobin gene.     

Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks?

Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy).We studied general and cancer related distress in 85 healthy women with a 25% or 50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the six to eight week period between genetic counselling/blood sampling and disclosure of the test result. Questionnaire and interview data are analysed. Associations are explored between levels of distress and (1) expected consequences of being identified as a mutation carrier, (2) personality traits, (3) sociodemographic variables, and (4) experiences related to HBOC.Mean pre-test anxiety and depression levels in women at risk of being a carrier and partners were similar to those of a normal Dutch population. In about 25% of those at risk of being a carrier and 10% of the partners, increased to high levels of general and cancer related distress were found. Increased levels of distress were reported by women who (1) anticipated an increase in problems after an unfavourable test outcome, (2) considered prophylactic mastectomy if found to be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress their emotions, (5) were younger than 40 years, and (6) were more familiar with the serious consequences of HBOC. Recently obtained awareness of the genetic nature of cancer in the family was not predictive of distress.The majority of the women and their partners experienced a relatively calm period before the disclosure of the test result and seemed to postpone distressing thoughts until the week of disclosure of the result. The low distress levels may partly be explained by the use of strategies to minimise the emotional impact of a possibly unfavourable test outcome. However, a minority reported feeling very distressed. Several factors were found to be predictive for increased distress levels.     

Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of “thyroid-checked” controls

A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4–14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of “thyroid-checked” controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.     

Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians

Variants in genes involved in pancreatic β-cell development and function are known to cause monogenic forms of type 2 diabetes and are also associated with complex form. In this study, we studied the genetic association of polymorphisms in such important genes with type 2 diabetes in the high-risk Indians. We genotyped 91 polymorphisms in 19 genes (ABCC8, HNF1A, HNF1B, HNF4A, INS, INSM1, ISL1, KCNJ11, MAFA, MNX1, NEUROD1, NEUROG3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1, USF1 and WFS1) in 2025 unrelated North Indians of Indo-European ethnicity comprising of 1019 diabetic and 1006 non-diabetic subjects. HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR)=1.37 (95% confidence interval (CI) 1.19-1.57), P=9.4 × 10(-6) for rs1884613 and OR=1.37 (95%CI 1.20-1.57), P=6.0 × 10(-6) for rs2144908), as previously shown in other populations. We observed body mass index-dependent association of these variants with type 2 diabetes in normal-weight/lean subjects. Variants in USF1, ABCC8, ISL1 and KCNJ11 showed nominal association, while haplotypes in these genes were significantly associated. rs3812704 upstream of NEUROG3 significantly increased risk for type 2 diabetes in normal-weight/lean subjects (OR=1.68 (95%CI 1.25-2.24), P=4.9 × 10(-4)). Thus, pancreatic β-cell development and function genes contribute to susceptibility to type 2 diabetes in North Indians.     

“Friending” Teens: Systematic Review of Social Media in Adolescent and Young Adult Health Care

Background

Social media has emerged as a potentially powerful medium for communication with adolescents and young adults around their health choices.

Objective

The goal of this systematic review is to identify research on the use of social media for interacting with adolescents and young adults in order to achieve positive health outcomes.

Methods

A MEDLINE/PubMed electronic database search was performed between January 1, 2002 and October 1, 2013, using terms to identify peer-reviewed research in which social media and other Web 2.0 technologies were an important feature. We used a systematic approach to retrieve papers and extract relevant data.

Results

We identified 288 studies involving social media, of which 87 met criteria for inclusion; 75 studies were purely observational and 12 were interventional. The ways in which social media was leveraged by these studies included (1) observing adolescent and young adult behavior (n=77), (2) providing health information (n=13), (3) engaging the adolescent and young adult community (n=17), and (4) recruiting research participants (n=23). Common health topics addressed included high-risk sexual behaviors (n=23), alcohol, tobacco, and other drug use (n=19), Internet safety (n=8), mental health issues (n=18), medical conditions (n=11), or other specified issues (n=12). Several studies used more than one social media platform and addressed more than one health-related topic.

Conclusions

Social media technologies offer an exciting new means for engaging and communicating with adolescents and young adults; it has been successfully used to engage this age group, identify behaviors, and provide appropriate intervention and education. Nevertheless, the majority of studies to date have been preliminary and limited in their methodologies, and mostly center around evaluating how adolescents and young adults use social media and the resulting implications on their health. Although these explorations are essential, further exploration and development of these strategies into building effective interventions is necessary.     

Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β-subunit

Heterodimeric hCG is one of the key hormones determining early pregnancy success. We have previously identified rare missense mutations in hCGβ genes with potential pathophysiological importance. The present study assessed the impact of these mutations on the structure and function of hCG by applying a combination of in silico (sequence and structure analysis, molecular dynamics) and in vitro (co-immunoprecipitation, immuno- and bioassays) approaches. The carrier status of each mutation was determined for 1086 North-Europeans [655 patients with recurrent miscarriage (RM)/431 healthy controls from Estonia, Finland and Denmark] using PCR-restriction fragment length polymorphism. The mutation CGB5 p.Val56Leu (rs72556325) was identified in a single heterozygous RM patient and caused a structural hindrance in the formation of the hCGα/β dimer. Although the amount of the mutant hCGβ assembled into secreted intact hCG was only 10% compared with the wild-type, a stronger signaling response was triggered upon binding to its receptor, thus compensating the effect of poor dimerization. The mutation CGB8 p.Pro73Arg (rs72556345) was found in five heterozygotes (three RM cases and two control individuals) and was inherited by two of seven studied live born children. The mutation caused ~50% of secreted β-subunits to acquire an alternative conformation, but did not affect its biological activity. For the CGB8 p.Arg8Trp (rs72556341) substitution, the applied in vitro methods revealed no alterations in the assembly of intact hCG as also supported by an in silico analysis. In summary, the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCGβ genes CGB5 and CGB8.     

Should genetic testing for BRCA1/2 be permitted for minors? Opinions of BRCA mutation carriers and their adult offspring

Although professional guidelines recommend against testing minors for adult-onset genetic conditions, the genetic testing of minors for BRCA1/2 alterations has been debated in the literature. To better understand the opinions of BRCA mutation carriers regarding the genetic testing of minors and the cognitive and affective processes underlying these opinions, we interviewed BRCA mutation carriers and their adult offspring who had learned of their parent's BRCA mutation. Semi-structured interviews were conducted with 53 parents and 22 offspring. In response to a closed-ended question, 52% (n = 39) of participants were opposed to the testing of minors. Responses to an open-ended question indicate that many participants (24%, n = 18) feel that testing could be permitted for some minor offspring. Psychological risks and the insufficient maturity of minors were frequent concerns of participants opposed to testing minors. The potential to impact health behaviors was frequently cited as a reason to support the genetic testing of minors. These preliminary results suggest that many BRCA mutation carriers and their adult offspring have concerns about, or are opposed to the genetic testing of minors. However, a significant minority in our study would support testing minors. Greater support for testing among offspring could indicate increasing requests for early genetic diagnosis. Further research is necessary to explore the risks and benefits of providing genetic testing to minors for adult-onset hereditary cancer syndromes in order to inform clinical practice and public policy and to ensure optimal psychosocial and medical outcomes for all members in families at risk for genetically determined disease.     

Is multiple SNP testing in BRCA2 and BRCA1 female carriers ready for use in clinical practice? Results from a large Genetic Centre in the UK

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82–1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33–0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.     

Genetic variants in PSEN2 and correlation to CSF β-amyloid42 levels in AD

Beta-amyloid 42 (Aβ42) concentrations in cerebrospinal fluid (CSF) are significantly decreased in Alzheimer's disease (AD). The aim of this study was to correlate genetic variability in presenilin 2 (PSEN2) in relation to Aβ42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF Aβ42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and Aβ42 levels. One distinct haploblock in PSEN2 was detected and the frequent haplotypes were analyzed using 4 tagging single nucleotide polymorphisms (SNPs). We found an association between haplotype 2 and higher CSF Aβ42 concentrations (p = 0.021) and lower Aβ42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower Aβ42 levels (p = 0.009). Additive regression analysis showed an association of Aβ42 level with APOE genotype (p = 0.024), haplotype 4 (p = 0.064), and haplotype 5 (p = 0.04), whereas gender, age at onset and Mini Mental State Examination (MMSE) remained insignificant. Using CSF Aβ42 as a biomarker we replicated genetic influences in APOE and observed a significant influence of a new haplotype in PSEN2. A better understanding of genetic influences on biomarkers like CSF Aβ42 might help to stratify patients and develop specific treatment strategies.     

Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function,and literature review

Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.     

BRCA1、BRCA2基因与乳腺癌、卵巢癌多发家族

目前研究普遍认为，BRCA1、BRCA2基因属抑癌基因，这些基因的某些突变型的携带者，患乳腺癌、卵巢癌等恶性肿瘤的危险性显著增高。本文介绍了BRCA1、BRCA2基因定位和克隆后，近年来对上述基因相关家族的特声、、基因外显年、抑癌机制、基因突变热点、突变类型的种族特异性等方面的研究进展，介绍了肿病高度和中反危险家族的划分方法和意义，并分析了今后我国在相关领域深入研究的思路。     

BRCA1,BRCA2基因与乳腺癌,卵巢癌多发家族

目前研究普遍认为,ＢＲＣＡ１,ＢＲＣＡ２基因属抑癌基因,这些基因的某些突变型的携带,患乳腺癌,卵巢癌等恶性肿瘤的危险性显增高,本介绍了ＢＲＣＡ１,ＢＲＣＡ２基因定位和克隆后,近年来对上述基因相关家族的特点,基因外显率,抑癌机制,基因突变热点,突变类型的种族特异性等方面的研究进展,介绍了肿瘤高度和中度危险家族的划分方法和意义,并分析了今后我国在相关领域深入研究的思路。