Rare Germline Mutations Research Articles

Increased incidence of bladder cancer, lymphoid leukaemia, and myeloma in a cohort of Queensland melanoma families

Familial cancer risk has been proposed as a shared feature of many cancers, and overall susceptibility is influenced by combinations of low to moderate risk polymorphisms, rare high penetrance germline mutations, and modulation of risk by environmental and genetic factors. Clustering of melanoma occurs in approximately 10% of families, and an over-representation of additional cancers has been noticed in some 'melanoma' families. The degree to which other cancers aggregate in families affected by melanoma has not been well defined. Therefore, this study aimed to assess the risk of cancers other than melanoma in a cohort of 178 'intermediate risk' melanoma families, not selected for specific genetic mutations. Families designated as 'intermediate risk' had two first degree relatives (FDRs) affected by melanoma when ascertained between 1982 and 1990, and were followed up over a 33year period to assess new occurrences of cancer. We included 414 melanoma cases and 529 FDRs, comprising 25,264 person years of observation. Standardised incidence ratios and their 95% confidence intervals were calculated for all invasive cancers, comparing observed to expected cases of cancer based on age and sex specific incidence rates for the Queensland population. Statistically significant increases were found for bladder cancer in females (observed, 7; expected, 1.99; SIR, 3.52; 95% CI 1.41-7.25), lymphoid leukaemia in females (observed, 6; expected, 1.75; SIR, 3.43; 95% CI 1.26-7.46), and myeloma in female melanoma cases (observed, 4; expected, 0.82; SIR, 4.89; 95% CI 1.33-12.52). Over-representation of bladder cancer, lymphoid leukaemia, and myeloma in females of the cohort may suggest sex-dependent co-modifiers, and it is possible that specific combinations of polymorphisms predispose to certain cancer types.

P53: out of Africa.

Somatic mutations in the tumor suppressor gene p53 occur in more than half of all human cancers. Rare germline mutations result in the Li-Fraumeni cancer family syndrome. In this issue ofGenes&Development, Jennis and colleagues (pp. 918-930) use an elegant mouse model to examine the affect of a polymorphism, P47S (rs1800371), in the N terminus of p53 that is found in Africans as well as more than a million African Americans. Remarkably, the single nucleotide change causes the mice to be substantially tumor-prone compared with littermates, suggesting that this allele causes an increased risk of developing cancer. The defect in p53 function is traced to a restriction in downstream gene regulation that reduces cell death in response to stress.

A new paradigm of genetic testing for hereditary breast/ovarian cancers.

Genetic risk factors and family history play an important role in breast cancer development. This review aimed to summarise the current genetic testing approach to hereditary breast/ovarian cancer. A systematic literature review was performed by searching the PubMed database. Publications available online until January 2015 that addressed issues related to hereditary breast/ovarian cancer genetic counselling/testing were selected. The search terms used were "familial breast/ovarian cancer", "susceptibility genes", "genetic counselling", and "genetic testing". The data extracted for this review were analysed by the authors, with a focus on genetic testing for hereditary breast/ovarian cancer. Although a greater proportion of inherited breast/ovarian cancers are due to the BRCA1 and BRCA2 mutations, a number of new genes have emerged as susceptibility candidates, including rare germline mutations in high penetrance genes, such as TP53 and PTEN, and more frequent mutations in moderate/low penetrance genes, such as PALB2, CHEK2 and ATM. Multi-gene testing, if used appropriately, is generally a more cost- and time-effective method than single-gene testing, and may increase the number of patients who can be offered personal surveillance, risk-reduction options, and testing of high-risk family members. Recent advances in molecular genetics testing have identified a number of susceptibility genes related to hereditary breast and/or ovarian cancers other than BRCA1 and BRCA2. The introduction of multi-gene testing for hereditary cancer has revolutionised the clinical management of high-risk patients and their families. Individuals with hereditary breast/ovarian cancer will benefit from genetic counselling/testing.

Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer

IntroductionThe association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants. MethodsTo search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking—37 of whom also exhibited carefully documented severe COPD (in whom smoking is considered the overwhelming determinant)—and 54 unique familial LC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects). ResultsBy focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1 was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine β-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4). ConclusionsOur results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.

Genetic predisposition to acute lymphoblastic leukemia: Overview on behalf of the I-BFM ALL Host Genetic Variation Working Group

Environmental causes of childhood acute lymphoblastic leukemia (ALL) remain largely undiscovered. In contrast, multiple germline ALL risk variants have been identified in the recent years. Apart from the low-risk common ALL risk alleles identified through genome wide association studies, rare germline mutations that cause cancer prone syndromes have been found to be associated with an increased risk of developing ALL. Here, we review the germline genetic changes known to be associated with ALL.

Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p.

Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72–84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.

Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.

Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500× coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients.

Abstract 4267: Integrated genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups

Abstract Hepatoblastoma (HB), the most common primary liver cancer in children, is a clinically heterogeneous embryonal malignancy. Previous studies of HB have revealed a paucity of genetic alterations in these tumors, other than mutations activating the WNT signaling pathway, and have not provided an adequate biological explanation for the diverse clinical outcomes of children with HB. To identify critical genes and pathways in the pathogenesis of HB and provide insight into the biologic basis and clinical heterogeneity of these tumors, we performed an integrated genomic analysis of a large cohort of clinically-annotated tumor-normal pairs utilizing whole exome sequencing (n = 35), mRNA and miRNA expression arrays (n = 51; n = 58), and high-resolution copy number arrays (n = 47). Somatic mutations/deletions of CTNNB1 or rare germline mutations of APC were identified in >90% of cases, confirming the central role of the WNT pathway in HB pathogenesis. The only other gene targeted by recurrent mutations in our cohort was the transcription factor NFE2L2 (NRF2), which was found to harbor hotspot mutations at a similar frequency (5-10%) to that reported for hepatocellular carcinoma. Expression profiling revealed near-universal WNT-pathway activation: 7 of the 20 most highly expressed genes in HB were WNT-pathway related genes, and the WNT-pathway marker DKK1 was expressed hundreds of standard deviations above its levels in normal liver. Unsupervised hierarchical clustering identified three distinct molecular HB clusters that were characterized by differential activation of hepatic progenitor cell and metabolic pathways. Analysis of the expression and/or inferred-activity of transcription factors and highly expressed genes identified prognostic biomarkers, including the significantly predictive regulons of NFE2L2, LIN28b, HNF1A, and NOTCH1. These were used to identify clinical groups that overlapped with HB expression clusters and were associated with patient survival. Tumors in the high-risk group were characterized by high NFE2L2, low NOTCH1 activity, and high LIN28b expression and activity (corresponding to low let-7b expression), as well as high expression of the onco-fetal proteins AFP and GPC3 and stem cell markers EPCAM, DLK1, and SALL4. In contrast, the low-risk group was characterized by high HNF1a and NOTCH1 activities and low LIN28 expression and activity. Rare chromosomal gains and losses were characteristic of the low risk group of tumors, while gains of 20q13 (SALL4) and 1q chromosomal regions were primarily found in the high and intermediate risk groups. Immunohistochemistry for LIN28b, NFE2L2, HNF1alpha, PTEN, and EPCAM is being performed on a validation set of tumors to assess their reliability to classify formalin-fixed tumor specimens. Prospective studies will test the prognostic utility of this method for children with HB. Citation Format: Dolores H. Lopez-Terrada, Pavel Sumazin, Yidong Chen, Lisa Trevino, Stephen Sarabia, Oliver Hampton, Kayuri Patel, Toni-Ann Mistretta, Barry Zorman, Sarah Comerford, David Wheeler, Murali Chintagumpala, Rebecka M. Meyers, Milton J. Finegold, Gail Tomlinson, Donald W. Parsons. Integrated genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4267. doi:10.1158/1538-7445.AM2015-4267

Beyond BRCA: new hereditary breast cancer susceptibility genes.

Approximately 5-10% of breast cancer cases might be inheritable, up to 30% of which are due to BRCA1/2 mutations. During the past few years and thanks to technology evolution, we have been witnesses of an intensive search of additional genes with similar characteristics, under the premise that successful gene discovery will provide substantial opportunities for primary and secondary prevention of breast cancer. Consequently, new genes have emerged as breast cancer susceptibility genes, including rare germline mutations in high penetrant genes, such as TP53 and PTEN, and more frequent mutations in moderate penetrant genes, such as CHEK2, ATM and PALB2. This review will summarize current data on new findings in breast cancer susceptibility genes.

Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas have a highly diverse genetic background, with a third of the cases carrying a germline mutation in 1 of 14 identified genes. This study aimed to evaluate next-generation sequencing for more efficient genetic testing of pheochromocytoma and paraganglioma and to establish germline and somatic mutation frequencies for all known susceptibility genes. A targeted next-generation sequencing approach on an Illumina MiSeq instrument was used for a mutation analysis in 86 unselected pheochromocytoma and paraganglioma tumor samples. The study included the genes EGLN1, EPAS1, KIF1Bβ, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. RESULTS were verified in tumor and constitutional DNA with Sanger sequencing. In all cases with clinical syndromes or known germline mutations, a mutation was detected in the expected gene. Among 68 nonfamilial tumors, 32 mutations were identified in 28 of the samples (41%), including germline mutations in EGLN1, KIF1Bβ, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1Bβ, MAX, NF1, RET, and VHL, including one double monoallelic EPAS1 mutation. Targeted next-generation sequencing proved to be fast and cost effective for the genetic analysis of pheochromocytoma and paraganglioma. More than half of the tumors harbored mutations in the investigated genes. Notably, 7% of the apparently sporadic cases carried germline mutations, highlighting the importance of comprehensive genetic testing. KIF1Bβ, which previously has not been investigated in a large cohort, appears to be an equally important tumor suppressor as MAX and TMEM127 and could be considered for genetic testing of these patients.

Low Frequency of Germline TERT and MITF Mutations in Brazilian Melanoma- Prone Patients

Recent studies have reported rare germline mutations affecting the MITF gene, and the promoter of the TERT gene in melanoma families. Here we looked at the prevalence of these rare penetrant mutations in a series of 48 patients (either familial melanoma or multiple melanomas), all of them negative for CDKN2A and CDK4 mutations. A single mutation was detected in a multiple melanoma patient, who was a heterozygous carrier of the E318K MITF variant. However, this variant was also detected in 1 out of 125 controls. This preliminary data points to a low frequency of MITF and TERT mutations in this Brazilian group of melanoma-prone patients.

PD-0298: IMPACT study - Targeted prostate cancer screening for rare germline mutation carriers

PD-0298: IMPACT study - Targeted prostate cancer screening for rare germline mutation carriers

Germline mutation in the RAD51B gene confers predisposition to breast cancer

BackgroundMost currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition.MethodsThe study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis.ResultsThree splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases.ConclusionsThis study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals.

DNA repair genes are selectively mutated in diffuse large B cell lymphomas

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.

Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas.

The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood. The possible role of cyclin-dependent kinase inhibitor (CDKI) genes was raised by recognition of cyclin D1 as a parathyroid oncogene, identification of rare germline mutations in CDKI genes in patients with multiple endocrine neoplasia type 1; that in rodents, mutation in Cdkn1b caused parathyroid tumors; and subsequently through identification of rare predisposing germline sequence variants and somatic mutation of CDKN1B, encoding p27(kip1), in sporadic human parathyroid adenoma. We therefore sought to determine whether mutations/variants in the other six CDKI genes CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and CDKN2D, encoding p21, p57, p14(ARF)/p16, p15, p18, and p19, respectively, contribute to the development of typical parathyroid adenomas. In a series of 85 sporadic parathyroid adenomas, direct DNA sequencing identified alterations in five adenomas (6%): Two contained distinct heterozygous changes in CDKN1A, one germline and one of undetermined germline status; one had a CDKN2B germline alteration, accompanied by loss of the normal allele in the tumor (LOH); two had variants of CDKN2C, one somatic and one germline with LOH. Abnormalities of three of the mutant proteins were readily demonstrable in vitro. Thus, germline mutations/rare variants in CDKN1A, CDKN2B, and CDKN2C likely contribute to the development of a significant subgroup of common sporadic parathyroid adenomas, and somatic mutation in CDKN2C further suggests a direct role for CDKI alteration in conferring a selective growth advantage to parathyroid cells, providing novel support for the concept that multiple CDKIs can play primary roles in human neoplasia.

Megalencephaly Syndromes and Activating Mutations in the PI3K‐AKT Pathway: MPPH and MCAP

AbstractThe megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) and megalencephaly‐capillary malformation (MCAP) syndromes are highly recognizable and partly overlapping disorders of brain overgrowth (megalencephaly). Both syndromes are characterized by congenital or early postnatal megalencephaly, with a high risk for progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria. MCAP is further characterized by distinct cutaneous capillary malformations, finger or toe syndactyly, postaxial polydactyly, variable connective tissue dysplasia and mild focal or segmental body overgrowth, among other features. MPPH, on the other hand, lacks consistent vascular or somatic manifestations besides postaxial polydactyly in almost half of reported individuals. We identified de novo germline mutations in PIK3R2 and AKT3 in individuals with MPPH, and both postzygotic, mosaic and rare germline mutations in PIK3CA in individuals with MCAP. PIK3R2, AKT3, and PIK3CA are members of the critical phosphatidylinositol‐3‐kinase (PI3K)‐vakt murine thymoma viral oncogene homolog (AKT) pathway that is well implicated in cell growth, proliferation, survival, apoptosis, among other diverse cellular functions. The identified mutations in these three genes have been shown to lead to gain of function and activation of the PI3K‐AKT pathway. Germline and postzygotic mutations of PIK3CA and other PI3K‐AKT‐mTOR pathway genes have also been identified in several other overgrowth syndromes, highlighting the key role of this signaling pathway in normal development and pathophysiology of a large group of congenital anomalies. © 2013 Wiley Periodicals, Inc.

Abstract 753: Reciprocal regulation of HOXB13 and androgen receptor in prostate cancer.

Abstract The androgen receptor (AR), a member of the nuclear receptor superfamily of ligand-regulated transcription factors, plays a pivotal role in the initiation and progression of prostate cancer. HOXB13, a prostate-specific homeodomain-containing transcription factor, interacts with AR to regulate the cellular response to androgens (Norris et al. Mol Cell 2009). Our group recently identified a rare but recurrent germline mutation (G84E) in HOXB13 as a prostate cancer susceptibility allele by sequencing the 17q21-22 region of the genomic DNA from families with hereditary prostate cancer. (Ewing et al. NEJM 2012). Our research goal is to study how HOXB13 regulates AR function and how this mechanism might be affected by mutant HOXB13. The overexpression of wild type HOXB13 in LNCaP cells led to an increased expression of AR at the mRNA and protein levels; this induction of AR was attenuated with HOXB13 G84E over-expression. Upon the reduction of endogenous HOXB13 by siRNA in LNCaP cells, the amount of AR decreased at the mRNA and protein levels, indicating that HOXB13 promotes the expression of AR. Conversely, when AR was knocked down with siRNA, the level of HOXB13 transcripts and proteins increased, indicating that AR suppresses HOXB13 expression. Furthermore, co-immunoprecipitation experiments demonstrate that FOXA1, the pioneer factor implicated to control prostate-specific transcription of HOXB13 (McMullin et al. 2009), interacts with AR and HOXB13. These analyses implicate at least a three factor mechanism whereby the levels of critical components of prostate-specific androgen signaling network might recruit and/or titrate one another, and suggest this network may be perturbed by mutations in HOXB13. Since LNCaP cells contain a mutated copy of HOXB13 (L144P), these analyses need to be performed in additional prostate cancer cells before general conclusions can be reached. Citation Format: Shuangling Chen, Dorhyun Johng, William B. Isaacs. Reciprocal regulation of HOXB13 and androgen receptor in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 753. doi:10.1158/1538-7445.AM2013-753

A dramatic lung cancer course in a patient with a rare EGFR germline mutation exon 21 V843I: Is EGFR TKI resistance predictable?

We report on the medical history of a Caucasian smoker woman diagnosed with a stage IV NSCLC adenocarcinoma, characterized by a rare epidermal growth factor receptor (EGFR) point mutation in exon 21 codon 843 (p.V843I/c.2527G>A/COSMIC ID 85894). This genetic alteration revealed to be germline, after its presence was demonstrated in chondroblasts from the bone biopsy. While it is the first description of germline V843I mutation without concomitant additional known EGFR activating mutation, we modeled the EGFR ATP catalytic domain in complex with ATP, gefitinib and erlotinib using computer-aided approaches to estimate possible changes in affinity upon the V843I mutation.

Hereditary Breast Cancer: The Era of New Susceptibility Genes

Breast cancer is the most common malignancy among females. 5%–10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered reference BRCA1 and BRCA2 genes. As sequencing technologies evolve, more susceptible genes have been discovered and BRCA1 and BRCA2 predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which include TP53 mutations in Li-Fraumeni syndrome, STK11 mutations in Peutz-Jeghers syndrome, and PTEN mutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such as CHEK2, ATM, PALB2, and BRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.

RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study

BackgroundAlthough inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.Methodology/Principal FindingsWe screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.ConclusionAltogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.