bims-lifras 2019-12-01 papers

bims-lifras

Biomed News

on Li-Fraumeni Syndrome

Issue of 2019‒12‒01
twenty-four papers selected by
Joanna Zawacka-Pankau

Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION SUMMARY, Number 793.
Hereditary prostate cancer - Primetime for genetic testing?
Spectrum and clinical relevance of PALB2 germline mutations in 7657 Chinese BRCA1/2-negative breast cancer patients.
MIR605 rs2043556 is associated with the occurrence of multiple primary tumors in TP53 p.(Arg337His) mutation carriers.
Genetic testing for hereditary gastrointestinal cancer syndromes: Interpreting results in today's practice.
Birt-Hogg-Dubé Syndrome-associated Renal Cell Carcinoma: Histopathological Features and Diagnostic Conundrum.
Assessment of ovarian reserve and reproductive outcomes in BRCA1 or BRCA2 mutation carriers.
Highly sensitive MLH1 methylation analysis in blood identifies a cancer patient with low-level mosaic MLH1 epimutation.
Genetic and clinical characterization of BRCA-associated hereditary breast and ovarian cancer in Navarra (Spain).
Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.
Prevalence and oncologic outcomes of BRCA1/2 mutation and variant of unknown significance in epithelial ovarian carcinoma patients in Korea.
A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect.
Low rates of cascade genetic testing among families with hereditary gynecologic cancer: An opportunity to improve cancer prevention.
Pancreatic Cancer Surveillance: Who, When, and How.
Effect of BRCA1 missense variants on gene reversion in DNA double-strand break repair mutants and cell cycle-arrested cells of Saccharomyces cerevisiae.
Patterns of germline and somatic mutations in 16 genes associated with mismatch repair function or containing tandem repeat sequences.
Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients.
Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).
Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel.
Use of Family History and Genetic Testing to Determine Risk of Colorectal Cancer.
Allele-specific expression mediates primary resistance to poly (ADP-ribose) polymerase inhibitor therapy in a case of BRCA1/2 double-germline mutant gastric cancer.
Do BRCA1 and BRCA2 gene mutation carriers have a reduced ovarian reserve? Protocol for a prospective observational study.
Identification of a novel germline BRCA2 variant in a Chinese breast cancer family.
Germline genetic variation in prostate susceptibility does not predict outcomes in the chemoprevention trials PCPT and SELECT.

Obstet Gynecol. 2019 Dec;134(6): 1366-1367

Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION SUMMARY, Number 793.

A hereditary cancer syndrome is a genetic predisposition to certain types of cancer, often with onset at an early age, caused by inherited pathogenic variants in one or more genes. Most hereditary cancer syndromes exhibit autosomal dominant inheritance. The most common hereditary cancer syndromes related to women's cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer. A hereditary cancer risk assessment is the key to identifying patients and families who may be at increased risk of developing certain types of cancer. Assessments should be performed by obstetrician-gynecologists or other obstetric-gynecologic care providers and should be updated regularly. An assessment includes information on personal and family history, including pathology, imaging reports, and evaluation of other medical risk factors for cancer. If a hereditary cancer risk assessment suggests an increased risk of a hereditary cancer syndrome, referral to a specialist in cancer genetics or a health care provider with expertise in genetics is recommended for expanded gathering of family history information, risk assessment, education, and counseling, which may lead to genetic testing and tailored cancer screening or risk reduction measures, or both. Currently, genetic testing is guided by personal history, family history, pedigree analysis and, in some cases, risk models that may include pathology reports and confirmation of cancer diagnoses with medical records, death certificates, or both. Counseling before and after genetic testing is an important part of the process to discuss rationale for any genetic testing, disclose results, define other cancer risks, identify educational needs, and secure referrals if necessary for ongoing management. This revision includes updates related to hereditary breast and ovarian cancer, cascade testing, and referrals to genetics specialists.

DOI: https://doi.org/10.1097/AOG.0000000000003563
Cancer Treat Rev. 2019 Nov 11. pii: S0305-7372(19)30146-X. [Epub ahead of print]81 101927

Hereditary prostate cancer - Primetime for genetic testing?

Heidegger I, Tsaur I, Borgmann H, Surcel C, Kretschmer A, Mathieu R, Visschere P, Valerio M, van den Bergh RCN, Ost P, Tilki D, Gandaglia G, Ploussard G, .

  Prostate cancer (PCa) remains the most common cancer in men. The proportion of all PCa attributable to high-risk hereditary factors has been estimated to 5-15%. Recent landmark discoveries in PCa genetics led to the identification of germline mutations/alterations (eg. BRCA1, BRCA2, ATM or HOXB13), single nucleotide polymorphisms or copy number variations associated with PCa incidence and progression. However, offering germline testing to men with an assumed hereditary component is currently controversial. In the present review article, we provide an overview about the epidemiology and the genetic basis of PCa predisposition and critically discuss the significance and consequence in the clinical routine. In addition, we give an overview about genetic tests and report latest findings from ongoing clinical studies. Lastly, we discuss the impact of genetic testing in personalized therapy in advanced stages of the disease.

Keywords:  Genetic testing; Hereditary; Precision oncology; Prostate cancer

DOI:  https://doi.org/10.1016/j.ctrv.2019.101927
Breast Cancer Res Treat. 2019 Nov 25.

Spectrum and clinical relevance of PALB2 germline mutations in 7657 Chinese BRCA1/2-negative breast cancer patients.

Wu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xu Y, Xie Y.

  PURPOSE: To investigate the prevalence and clinical relevance of PALB2 germline mutations in BRCA1/2-negative breast cancer patients.METHODS: The exons and intron-exon boundaries of the PALB2 gene were sequenced by multigene panel testing in a cohort of 7657 Chinese BRCA1/2-negative breast cancer patients.
RESULTS: Of the 7657 patients, 54 (0.71%) carried pathogenic PALB2 germline mutations, all of which were nonsense or frameshift mutations leading to a truncated protein. The 54 patients carried 42 distinct pathogenic mutations, of which 17 (40.5%) were novel and 8 were recurrent mutations. Compared with non-carriers, PALB2 pathogenic mutation carriers developed breast cancer at a younger age (47.52 years vs. 51.35 years, p = 0.016) and were more likely to have triple-negative (24.1% vs. 13.4%, p = 0.022) or HER2 negative (87.0% vs. 74.2%, p = 0.031) breast cancer and large breast tumors (> 2 cm) at diagnosis (72.2% vs. 57.0%, p = 0.024). PALB2 mutation carriers were also more likely to have family histories of breast and/or ovarian cancer (27.8% vs. 8.4%, p < 0.001) and any types of cancer (57.4% vs. 31.6%, p < 0.001) when compared with non-carriers.
CONCLUSIONS: PALB2 germline mutations are present at 0.71% in Chinese BRCA1/2-negative breast cancer patients and are more frequent in patients with triple-negative breast cancer and family histories of breast and/or ovarian cancer.

Keywords:  BRCA negative; Breast cancer; Germline mutation; PALB2

DOI:  https://doi.org/10.1007/s10549-019-05483-7
Cancer Genet. 2019 Nov 20. pii: S2210-7762(19)30438-7. [Epub ahead of print]240 54-58

MIR605 rs2043556 is associated with the occurrence of multiple primary tumors in TP53 p.(Arg337His) mutation carriers.

Bandeira IC, Vieira IA, Andreis TF, Brussa Reis L, Macedo GS, Vianna FSL, Santos-Silva P, Palmero EI, Galvão HCR, Ramos CRN, Santiago KM, Achatz MI, da Costa AABA, Ashton-Prolla P.

  Li-Fraumeni and Li-Fraumeni-like (LFS/LFL) Syndrome are cancer predisposition syndromes caused by germline pathogenic variants in TP53 and are associated with an increased risk of multiple early-onset cancers. In Southern and Southeastern Brazil, a germline founder variant with partial penetrance located in the oligomerization domain of TP53, c.1010G>A p.(Arg337His, commonly known as R337H), has been detected in 0.3% of the general population. Recently, the functional MIR605 variant rs2043556 (A>G) has been identified as a novel LFS phenotype modifier in families with germline TP53 DNA binding variants. In this study, our goal was to verify MIR605 rs2043556 allele frequencies and further explore its possible effects on the phenotype of 238 Brazilian individuals carrying TP53 p.(Arg337His). The MIR605 rs2043556 G allele was detected in 136 (57.1%) individuals, including 25 homozygotes (10.5%), and although it had been previously associated with an earlier mean age of tumor onset, this effect was not observed in this study (p = 0.8). However, in p.(Arg337His) mutation carriers, the GG genotype was significantly associated with the occurrence of multiple primary tumors (p = 0.005). We provide further evidence of MIR605 rs2043556 G allele's effect as a phenotype modulator in carriers of germline TP53 pathogenic variants.

Keywords:  Li-Fraumeni Syndrome; MIR605 gene; Multiple primary tumors; rs2043556

DOI:  https://doi.org/10.1016/j.cancergen.2019.11.005
Curr Treat Options Gastroenterol. 2019 Nov 25.

Genetic testing for hereditary gastrointestinal cancer syndromes: Interpreting results in today's practice.

Powers JM, Ebrahimzadeh JE, Katona BW.

  PURPOSE OF REVIEW: Advances in genomics have led to the discovery of multiple predisposition genes linked to increased risk for gastrointestinal (GI) cancer. The goal of this review is to assist physicians and allied health care professionals in understanding the current paradigm shift in clinical genetic testing for hereditary GI cancer predisposition syndromes; with a focus on multigene panel testing (MGPT) and test results interpretation. Additionally, this review introduces direct-to-consumer and at-home genetic testing. Both delivery models are increasing in popularity and clinicians will be expected to address results from patients who utilize these approaches.RECENT FINDINGS: Technological advancement and reduced costs have transformed the genetic testing approach from single syndrome genetic testing to broad-based MGPT. MGPT has the benefit of aiding in efficient genetic diagnosis; however, clinicians should be knowledgeable of possible results including variants of uncertain significance, secondary findings, and pathogenic variants within high- and low-to-moderate risk genes, as well as genes for which risks are ill-defined. The landscape of clinical cancer genetics continues to evolve rapidly. Timely updates are critical to ensure the medical community is familiar with current considerations and ongoing challenges regarding genetic testing for hereditary GI cancer susceptibility.

Keywords:  Multigene panel testing; cancer genetics; direct-to-consumer; gastrointestinal cancer susceptibility; genetics; variant interpretation

DOI:  https://doi.org/10.1007/s11938-019-00253-2
Cancer Sci. 2019 Nov 28.

Birt-Hogg-Dubé Syndrome-associated Renal Cell Carcinoma: Histopathological Features and Diagnostic Conundrum.

Furuya M, Hasumi H, Yao M, Nagashima Y.

  Birt-Hogg-Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome-associated RCC (BHD-RCC) are less aggressive and multifocal. Therefore, it is critical to distinguish BHD-RCC from its sporadic counterparts to identify and monitor affected families and to preserve renal function as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCCs; however, BHD-RCC was not included in this classification. Although the clinical features and molecular mechanisms of BHD-RCC have been investigated intensively over the last two decades, pathologists and urologists occasionally face difficulties in the diagnosis of BHD-RCCs that require genetic testing. Affected patients usually have miscellaneous benign disorders that often precede renal carcinogenesis. In the present review, we summarize the current understanding of the histopathological features of BHD-RCC based on our epidemiologic studies of Japanese families and a literature review. The pathological diagnostic clues and differential diagnosis of BHD-RCC from other hereditary RCCs are also briefly discussed.

Keywords:  Birt-Hogg-Dubé (BHD) syndrome; folliculin (FLCN); hereditary cancer; histopathology; renal cell carcinoma (RCC)

DOI:  https://doi.org/10.1111/cas.14255
Int J Gynecol Cancer. 2019 Nov 27. pii: ijgc-2019-000626. [Epub ahead of print]

Assessment of ovarian reserve and reproductive outcomes in BRCA1 or BRCA2 mutation carriers.

Ponce J, Fernandez-Gonzalez S, Calvo I, Climent M, Peñafiel J, Feliubadaló L, Teulé A, Lázaro C, Brunet JM, Candás-Estébanez B, Durán Retamal M.

  INTRODUCTION: The clinical impact on fertility in carriers of BRCA1 and BRCA2 mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels in BRCA1 or BRCA2 mutation carriers, as well as to investigate the impact of anti-mullerian hormone levels on reproductive outcomes.METHODS: The study involved a cohort of women who tested positive for BRCA1 and BRCA2 screening or were tested for a BRCA1 or BRCA2 family mutation. Blood samples were collected for anti-mullerian hormone analysis and the reproductive outcomes were analyzed after a mean follow-up of 9 years. Participants were classified into BRCA mutation-positive versus BRCA mutation-negative. Controls were healthy relatives who tested negative for the family mutation. All patients were contacted by telephone to collect data on reproductive outcomes. Linear regression was used to predict anti-mullerian hormone levels by BRCA status adjusted for a polynomial form of age.
RESULTS: Results of anti-mullerian hormone analysis and reproductive outcomes were available for 135 women (BRCA mutation-negative, n=66; BRCA1 mutation-positive, n=32; BRCA2 mutation-positive, n=37). Anti-mullerian hormone curves according to BRCA status and adjusted by age showed that BRCA2 mutation-positive patients have lower levels of anti-mullerian hormone as compared with BRCA-negative and BRCA1 mutation-positive. Among the women who tried to conceive, infertility was observed in 18.7% of BRCA mutation-negative women, in 22.2% of BRCA1 mutation-positive women, and in 30.8% of BRCA2 mutation-positive women (p=0.499). In the multivariable analysis, there were no factors independently associated with infertility.
DISCUSSION: BRCA2 mutation-positive carriers showed more diminished anti-mullerian hormone levels than BRCA1 mutation-positive and BRCA mutation-negative women. However, these differences do not appear to have a negative impact on reproductive outcome. This is important to consider at the time of reproductive counseling in women with BRCA1 or BRCA2 mutations.

Keywords:  BCRA1; BCRA2; anti-Müllerian hormone; fertility; ovarian reserve; reproduction

DOI:  https://doi.org/10.1136/ijgc-2019-000626
Clin Epigenetics. 2019 Nov 28. 11(1): 171

Highly sensitive MLH1 methylation analysis in blood identifies a cancer patient with low-level mosaic MLH1 epimutation.

Dámaso E, Canet-Hermida J, Vargas-Parra G, Velasco À, Marín F, Darder E, Del Valle J, Fernández A, Izquierdo À, Mateu G, Oliveras G, Escribano C, Piñol V, Uchima HI, Soto JL, Hitchins M, Farrés R, Lázaro C, Queralt B, Brunet J, Capellá G, Pineda M.

  Constitutional MLH1 methylation (epimutation) is a rare cause of Lynch syndrome. Low-level methylation (≤ 10%) has occasionally been described. This study aimed to identify low-level constitutional MLH1 epimutations and determine its causal role in patients with MLH1-hypermethylated colorectal cancer.Eighteen patients with MLH1-hypermethylated colorectal tumors in whom MLH1 methylation was previously undetected in blood by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were screened for MLH1 methylation using highly sensitive MS-melting curve analysis (MS-MCA). Constitutional methylation was characterized by different approaches.MS-MCA identified one patient (5.6%) with low-level MLH1 methylation (~ 1%) in blood and other normal tissues, which was confirmed by clonal bisulfite sequencing in blood. The patient had developed three clonally related gastrointestinal MLH1-methylated tumor lesions at 22, 24, and 25 years of age. The methylated region in normal tissues overlapped with that reported for other carriers of constitutional MLH1 epimutations. Low-level MLH1 methylation and reduced allelic expression were linked to the same genetic haplotype, whereas the opposite allele was lost in patient's tumors. Mutation screening of MLH1 and other hereditary cancer genes was negative.Herein, a highly sensitive MS-MCA-based approach has demonstrated its utility for the identification of low-level constitutional MLH1 epigenetic mosaicism. The eventual identification and characterization of additional cases will be critical to ascertain the cancer risks associated with constitutional MLH1 epigenetic mosaicism.

Keywords:  Constitutional MLH1 epimutation; Epigenetic mosaicism; Highly sensitive methodologies; Lynch syndrome; Methylation

DOI:  https://doi.org/10.1186/s13148-019-0762-6
BMC Cancer. 2019 Nov 27. 19(1): 1145

Genetic and clinical characterization of BRCA-associated hereditary breast and ovarian cancer in Navarra (Spain).

Ruiz de Sabando A, Urrutia Lafuente E, García-Amigot F, Alonso Sánchez A, Morales Garofalo L, Moreno S, Ardanaz E, Ramos-Arroyo MA.

  BACKGROUND: Genetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC). The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community.METHODS: The study includes 1246 individuals assessed for BRCA1/2 genetic testing in Navarra, during 2000-2016, and a cohort of BC (n = 4384) and OC (n = 561) from the population-based Navarra Cancer Registry. Distribution and molecular characteristics of BRCA1/2 mutations, as well as, comparative analysis of the clinical course, pathologic features and overall survival (OS) of patients in different risk groups were investigated.
RESULTS: BRCA mutation detection rate was 16%, with higher proportion (63%) of BRCA2 families. Nineteen per cent of mutations were recurrent, one of which, BRCA2 c.6024dupG, showed high association to OC. BRCA carriers had double risk (95% CI = 1.04-4.33) of developing multiple malignancies than low risk families and were diagnosed at a much earlier age (16.6 and 11.7 years difference for BC and OC, respectively) when compared to the general population. For BC, BRCA carriers showed a more advanced histological stage, higher risk of bilateral neoplasms (OR = 4.3; 95% CI = 1.3-11.4, for BRCA2 carriers) and worse OS rate at 5-, 10- and 15- years, than women with sporadic tumors. For OC, over 70% of patients of all risk groups showed advanced stages at diagnosis, with the highest among BRCA1 carriers (91%). Furthermore, they also had higher probability of developing ovarian bilateral tumors (OR = 7.8, 95% CI = 1.7-55.7, for BRCA1 carriers) than the general population. Five-year OS rate was worse among women with sporadic OC than BRCA carriers, but it levelled out over the 15-year period.
CONCLUSIONS: In addition to national similarities in the HBOC-BRCA1/2 associated mutational spectrum, we identified a recurrent BRCA2 pathogenic variant (c.6024dupG), highly associated to OC in Navarra. Carriers of BRCA1/2 mutations showed a more severe BC and OC phenotype and had a worse overall prognosis when compared to a large cohort of women with sporadic counterpart tumors.

Keywords:  BRCA1/2; Demographics; Hereditary breast and ovarian cancer (HBOC); Laterality and stage of tumors; Navarra; Overall survival; Recurrent mutations; Sporadic breast and ovarian cancer

DOI:  https://doi.org/10.1186/s12885-019-6277-x
Sci Rep. 2019 Nov 28. 9(1): 17769

Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.

Dutil J, Teer JK, Golubeva V, Yoder S, Tong WL, Arroyo N, Karam R, Echenique M, Matta JL, Monteiro AN.

Inherited pathogenic variants in genes that confer moderate to high risk of breast cancer may explain up to 50% of familial breast cancer. This study aimed at identifying inherited pathogenic variants in breast cancer cases from Puerto Rico that were not linked to BRCA1 or BRCA2. Forty-eight breast cancer patients that met the clinical criteria for BRCA testing but had received a negative BRCA1/2 result were recruited. Fifty-three genes previously implicated in hereditary cancer predisposition were captured using the BROCA Agilent cancer risk panel followed by massively parallel sequencing. Missense variants of uncertain clinical significance in CHEK2 were evaluated using an in vitro kinase assays to determine their impact on function. Pathogenic variants were identified in CHEK2, MUTYH, and RAD51B in four breast cancer patients, which represented 8.3% of the cohort. We identified three rare missense variants of uncertain significance in CHEK2 and two variants (p.Pro484Leu and p.Glu239Lys) showed markedly decreased kinase activity in vitro comparable to a known pathogenic variant. Interestingly, the local ancestry at the RAD51B locus in the carrier of p.Arg47* was predicted to be of African origin. In this cohort, 12.5% of the BRCA-negative breast cancer patients were found to carry a known pathogenic variant or a variant affecting protein activity. This study reveals an unmet clinical need of genetic testing that could benefit a significant proportion of at-risk Latinas. It also highlights the complexity of Hispanic populations as pathogenic factors may originate from any of the ancestral populations that make up their genetic backgrounds.

DOI: https://doi.org/10.1038/s41598-019-54170-6
Obstet Gynecol Sci. 2019 Nov;62(6): 411-419

Prevalence and oncologic outcomes of BRCA1/2 mutation and variant of unknown significance in epithelial ovarian carcinoma patients in Korea.

Seo JH, Jeong SY, Kim MS, Kang JH, Paik ES, Lee YY, Kim TJ, Lee JW, Kim BG, Bae DS, Choi CH.

  Objective: BRCA mutational status is important in the management of ovarian cancer, but there is a lack of evidence supporting genetic testing in Asian populations. This study was performed to investigate the prevalence and prognostic outcomes of BRCA1/2 mutation and variant of unknown significance (VUS) in Korean patients diagnosed with epithelial ovarian cancer (EOC).Methods: Among patients newly diagnosed with EOC between January 2007 and January 2017, those tested for germline BRCA1/2 mutation were studied, regardless of family history. Overall survival (OS) and progression-free survival (PFS) were compared between the patients with and without BRCA1/2 mutation and VUS.
Results: A total of 313 patients underwent BRCA testing: 88 patients had a BRCA1/2 mutation and 48 patients had a BRCA1/2 VUS (28.1% and 15.3%, respectively). There were no significant associations between BRCA1/2 mutation, BRCA1/2 wild-type, or BRCA1/2 VUS with age at diagnosis, histologic distribution, or residual disease status after primary cytoreductive surgery. BRCA1 mutation, including BRCA1 VUS, showed no difference in PFS or OS compared to BRCA1 wild-type. In contrast, BRCA2 mutation showed longer PFS than that of BRCA2 wild-type (P=0.04) or BRCA2 VUS (P=0.02). BRCA2 mutation, including BRCA2 VUS, did not show any difference in OS compared to BRCA2 wild-type.
Conclusion: BRCA mutation and BRCA VUS had similar clinical characteristics and survival outcomes, except that BRCA2 mutation showed better PFS. The results of this study will help to understand the prognostic significance of BRCA mutation and VUS in Korean patients.

Keywords:  BRCA1 gene; BRCA2 gene; Epithelial ovarian cancer; Variant of unknown significance

DOI:  https://doi.org/10.5468/ogs.2019.62.6.411
Mol Genet Genomic Med. 2019 Nov 28. e1070

A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect.

Dawson LM, Smith KN, Werdyani S, Ndikumana R, Penney C, Wiede LL, Smith KL, Pater JA, MacMillan A, Green J, Drover S, Young TL, O'Rielly DD.

  BACKGROUND: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer.METHODS: Five female HBOC probands sequenced negative for moderate- and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors.
RESULTS: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function.
CONCLUSION: The RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re-classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.

Keywords:  RAD51C; founder variant; hereditary breast and ovarian cancer; splicing; variant of uncertain significance

DOI:  https://doi.org/10.1002/mgg3.1070
Gynecol Oncol. 2019 Nov 25. pii: S0090-8258(19)31626-9. [Epub ahead of print]

Low rates of cascade genetic testing among families with hereditary gynecologic cancer: An opportunity to improve cancer prevention.

Griffin NE, Buchanan TR, Smith SH, Leon AA, Meyer MF, Liu J, Tabak RG, Fuh KC, Thaker PH, Powell MA, Mutch DG, Massad LS, Colditz GA, Hagemann AR.

OBJECTIVE: Cascade genetic testing (CGT) of hereditary breast and ovarian cancer (HBOC) or Lynch Syndrome (LS) patients' relatives offers opportunities to prevent cancer, but CGT rates are not well described. We aimed to measure reported disclosure of genetic testing results and CGT rates in these families and evaluate patients' views of educational media.METHODS: Patients with HBOC or LS identified from germline genetic testing at an academic institution between 2011 and 2016 were surveyed regarding disclosure, testing among relatives, and perceptions of educational materials. Medical records and pedigrees provided numbers of total and first-degree relatives.
RESULTS: Of 103 mutation carriers consented, 64 (63%) completed the survey an average of 38 months after receiving genetic testing results. Participants' mean age was 53 years, and thirty-one (48%) had a cancer diagnosis. The majority (86%) felt extremely or very comfortable sharing health information. Participants disclosed results to 87% of first-degree relatives, but reported that only 40% of first-degree relatives underwent testing. First-degree female relatives had significantly higher CGT rates than first-degree male relatives (59% versus 21%, P < 0.001). Participants with HBOC reported higher CGT rates than those with LS (49% versus 33%, P = 0.02). Participants did not identify any one educational medium as more helpful than the others for disclosing results.
CONCLUSION: Disclosure rates are high among HBOC and LS mutation carriers, but reported CGT rates are low. Gender- and mutation-specific barriers prevent patients' family members from undergoing CGT. Future studies should implement materials to address these barriers and improve CGT rates.

DOI: https://doi.org/10.1016/j.ygyno.2019.11.005
Curr Treat Options Gastroenterol. 2019 Nov 24.

Pancreatic Cancer Surveillance: Who, When, and How.

Dudley B, Brand RE.

  PURPOSE OF REVIEW: Individuals who have an increased risk for pancreatic cancer (PC) due to personal or family history may benefit from surveillance of the pancreas to increase the likelihood of early detection. This review explores current indications for PC surveillance, as well as options for surveillance modality and timing, and data regarding surveillance outcomes.RECENT FINDINGS: Recently published data suggests that individuals undergoing surveillance who develop PC are more likely to be diagnosed with resectable disease, which improves survival. Several professional organizations have published guidelines for surveillance to help define who should have surveillance, when surveillance should be performed, and how it can be accomplished. PC surveillance should be considered for individuals with a pathogenic variant in a PC-related gene who have an affected first- or second-degree relative and for individuals in a familial pancreatic cancer family who have an affected first-degree relative. Surveillance should begin at age 50, or 10 years before the earliest age of PC diagnosis in the family. Endoscopic ultrasound (EUS) or MRI/MRCP are both reasonable surveillance options, but EUS may be better at detecting small solid changes in the pancreas. Ideally, surveillance should be performed at expert centers in conjunction with research protocols.

Keywords:  Endoscopic ultrasound; Pancreatic cancer; Pancreatic cancer genetic predisposition; Pancreatic cancer surveillance

DOI:  https://doi.org/10.1007/s11938-019-00247-0
Mutagenesis. 2019 Nov 26. pii: gez043. [Epub ahead of print]

Effect of BRCA1 missense variants on gene reversion in DNA double-strand break repair mutants and cell cycle-arrested cells of Saccharomyces cerevisiae.

Lodovichi S, Bellè F, Cervelli T, Lorenzoni A, Maresca L, Cozzani C, Caligo MA, Galli A.

Evaluation of the functional impact of germline BRCA1 variants that are likely to be associated to breast and ovarian cancer could help to investigate the mechanism of BRCA1 tumorigenesis. Expression of pathogenic BRCA1 missense variants increased homologous recombination (HR) and gene reversion (GR) in yeast. We thought to exploit yeast genetics to shed light on BRCA1-induced genome instability and tumorigenesis. We determined the effect on GR of several neutral and pathogenic BRCA1 variants in the yeast strain RSY6wt and its isogenic DSB repair mutants, such as mre11∆, rad50∆ and rad51∆. In the RSY6wt, four out of five pathogenic and two out of six neutral variants significantly increased GR; rad51∆ strain, the pathogenic variants C61G and A1708E induced a weak but significant increase in GR. On the other hand, in rad50∆ mutant expressing the pathogenic variants localised at the BRCT domain, a further GR increase was seen. The neutral variant N132K and the VUS A1789T induced a weak GR increase in mre11∆ mutant. Thus, BRCA1 missense variants require specific genetic functions and presumably induced GR by different mechanisms. As DNA repair is regulated by cell cycle, we determined the effect on GR of BRCA1 variants in cell cycle-arrested RSYwt cells. GR is highly BRCA1-inducible in S-phase-arrested cells as compared to G1 or G2. Sequence analysis of genomic DNA from ILV1 revertant clones showed that BRCA1-induced ilv1-92 reversion by base substitution when GR is at least 6-fold over the control. Our study demonstrated that BRCA1 may interfere with yeast DNA repair functions that are active in S-phase causing high level of GR. In addition, we confirmed here that yeast could be a reliable model to investigate the mechanism and genetic requirements of BRCA1-induced genome instability. Finally, developing yeast-based assays to characterise BRCA1 missense variants could be useful to design more precise therapies.

DOI: https://doi.org/10.1093/mutage/gez043
Cancer Med. 2019 Nov 25.

Patterns of germline and somatic mutations in 16 genes associated with mismatch repair function or containing tandem repeat sequences.

Chang SC, Lan YT, Lin PC, Yang SH, Lin CH, Liang WY, Chen WS, Jiang JK, Lin JK.

  BACKGROUND: We assumed that targeted next-generation sequencing (NGS) of mismatch repair-associated genes could improve the detection of driving mutations in colorectal cancers (CRC) with microsatellite instability (MSI) and microsatellite alterations at selected tetranucleotide repeats (EMAST) and clarify the somatic mutation patterns of CRC subtypes.MATERIAL AND METHODS: DNAs from tumors and white blood cells were obtained from 81 patients with EMAST(+)/MSI-high (MSI-H), 78 patients with EMAST(+)/microsatellite stable (MSS), and 72 patients with EMAST(-)/MSI-H. The germline and somatic mutations were analyzed with a 16-genes NGS panel.
RESULTS: In total, 284 germline mutations were identified in 161 patients. The most common mutations were in EPCAM (24.8%), MSH6 (24.2%), MLH1 (21.7%), and AXIN2 (21.7%). Germline mutations of AXIN2, POLE, POLD1, and TGFBR2 also resulted in EMAST and MSI. EMAST(+)/MSI-H tumors had a significant higher mutation number (205.9 ± 95.2 mut/MB) than tumors that were only EMAST(+) or MSI-H (118.6 ± 64.2 and 106.2 ± 54.5 mut/MB, respectively; both P < .001). In patients with AXIN2 germline mutations, the number of pathological somatic mutations in the tumors was significantly higher than those without AXIN2 germline mutations (176.7 ± 94.2 mut/MB vs 139.6 ± 85.0 mut/MB, P = .002).
CONCLUSION: Next-generation sequencing could enhance the detection of familial CRC. The somatic mutation burden might result from not only the affected genes in germline mutations but also through the dysfunction of downstream effectors. The AXIN2 gene might associate with hypermutation in tumors. Further in vitro experiments to confirm the causal relationship is deserved.

Keywords:  EMAST; MMR; MSI; colorectal cancer; mutation

DOI:  https://doi.org/10.1002/cam4.2702
Sci Rep. 2019 Nov 28. 9(1): 17808

Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients.

Sugino K, Tamura R, Nakaoka H, Yachida N, Yamaguchi M, Mori Y, Yamawaki K, Suda K, Ishiguro T, Adachi S, Isobe M, Yamaguchi M, Kashima K, Motoyama T, Inoue I, Yoshihara K, Enomoto T.

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

DOI: https://doi.org/10.1038/s41598-019-54116-y
Gut. 2019 Nov 28. pii: gutjnl-2019-319915. [Epub ahead of print]

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).

Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J, .

  Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

Keywords:  colorectal cancer; colorectal surgery; genetic testing; inherited cancers; surveillance

DOI:  https://doi.org/10.1136/gutjnl-2019-319915
J Med Genet. 2019 Nov 29. pii: jmedgenet-2019-106403. [Epub ahead of print]

Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel.

Lerner-Ellis J, Sopik V, Wong A, Lázaro C, Narod SA, Charames GS.

  BACKGROUND: The value of retesting women who previously tested negative for a pathogenic variant (mutation) in BRCA1 and BRCA2 using an expanded panel of breast and ovarian cancer genes is unclear.METHODS: We studied 110 BRCA1/2-negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for BRCA pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician.
RESULTS: Overall, six pathogenic variants in genes other than BRCA1 and BRCA2 were found (prevalence 5.5%). There were two pathogenic variants found in RAD51C, and one found in each of BRIP1, PALB2, PMS2 and PTEN. The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance.
CONCLUSIONS: Our findings indicate that the retesting of BRCA1/2-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than BRCA1 and BRCA2.

Keywords:  BRCA1/2 negative; gene panel; hereditary breast and ovarian cancer; retesting

DOI:  https://doi.org/10.1136/jmedgenet-2019-106403
Gastroenterology. 2019 Nov 21. pii: S0016-5085(19)41585-0. [Epub ahead of print]

Use of Family History and Genetic Testing to Determine Risk of Colorectal Cancer.

Kastrinos F, Samadder NJ, Burt RW.

  Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease, due to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5%-10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes-this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes, based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.

Keywords:  Colorectal Cancer Genetic Risk Assessment; Familial Colorectal Cancer; Inherited Colorectal Cancer Syndromes

DOI:  https://doi.org/10.1053/j.gastro.2019.11.029
J Int Med Res. 2019 Nov 27. 300060519886226

Allele-specific expression mediates primary resistance to poly (ADP-ribose) polymerase inhibitor therapy in a case of BRCA1/2 double-germline mutant gastric cancer.

Wen L, Li X, Shi J, Zhang S, Wang R, Yao M, Guo J.



Keywords:  BRCA1/2; Gastric cancer; PARP inhibitor; allele specific expression; olaparib; resistance

DOI:  https://doi.org/10.1177/0300060519886226
BMJ Open. 2019 Nov 25. 9(11): e033810

Do BRCA1 and BRCA2 gene mutation carriers have a reduced ovarian reserve? Protocol for a prospective observational study.

Winship AL, Willson C, Hansen KR, Hutt KJ, Hickey M.

  INTRODUCTION: BRCA1/2 gene mutations increase risk of breast and/or ovarian cancer and may have implications for reproductive health. Indirect biomarkers of the ovarian primordial follicle pool (anti-Müllerian hormone (AMH)) and one small study in female cadavers suggest that ovarian reserve may be reduced in BRCA mutation carriers, but findings are conflicting and association between circulating AMH and primordial follicle number is not established. The aim of this study is to measure primordial follicle density in premenopausal ovarian tissue samples from women with BRCA1/2 gene mutations versus age-matched comparison group.METHODS AND ANALYSIS: Prospective observational study measuring associations between BRCA gene mutation status, premenopausal ovarian primordial follicle density and serum AMH concentrations versus age-matched premenopausal women from the general population. Primordial follicle density will be measured in cortical sections from ovarian tissue collected at the time of risk-reducing bilateral salpingo-oophorectomy (RRBSO) in 88 BRCA1 gene mutation carriers, 65 BRCA2 gene mutation carriers and 157 non-mutation carriers. Primordial follicle density will be determined by counting follicles in a known volume of ovarian cortical tissue using light microscopy. Follicles will be identified by immunohistochemical staining for oocyte marker mouse vasa homologue. To inform the mechanisms underlying reduced ovarian reserve, the proportion of follicles containing oocytes with DNA damage will be determined by immunohistochemical staining for phosphorylated histone H2AX and terminal deoxynucleotidyl transferase dUTP nick end labelling assay to identify apoptotic cells. Follicle density will be correlated with circulating AMH concentrations quantified in the same cohort, using an electrochemiluminescence immunoassay on an automated platform.
ETHICS AND DISSEMINATION: Ethics approval has been granted by Peter MacCallum Cancer Centre to access biobanks, including; The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab-HREC#97_27) and the What Happens after Menopause? (HREC12PMCC24-12/90) and Melbourne IVF.

Keywords:  BRCA; DNA repair; fertility; follicle; germline mutation; oocyte

DOI:  https://doi.org/10.1136/bmjopen-2019-033810
J Cell Mol Med. 2019 Nov 28.

Identification of a novel germline BRCA2 variant in a Chinese breast cancer family.

Cheng J, Peng J, Fu J, Khan MA, Tan P, Wei C, Deng X, Chen H, Fu J.

  Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths in women worldwide. In this study, a large Chinese pedigree with breast cancer including a proband and two female patients was recruited and a familial history of breast cancer was collected by questionnaire. Clinicopathological assessments and neoadjuvant therapy-related information were obtained for the proband. Blood samples were taken, and gDNA was extracted. The BRCA1/2 and PALB2 genes were screened using next-generation sequencing by a targeted gene panel. We have successfully identified a novel, germline heterozygous, missense mutation of the gene BRCA2: c.7007G>T, p.R2336L, which is likely to be pathogenic in the proband and her elder sister who both had breast cancer. Furthermore, the risk factors for developing breast cancer in this family are discussed. Thus, genetic counselling and long-term follow-up should be provided for this family of breast cancer patients as well as carriers carrying a germline variant of BRCA2: c.7007G>T (p.R2336L).

Keywords:  BRCA2; breast cancer; genetic counselling; germline; missense mutation; risk factors

DOI:  https://doi.org/10.1111/jcmm.14861
Prostate Cancer Prostatic Dis. 2019 Nov 27.

Germline genetic variation in prostate susceptibility does not predict outcomes in the chemoprevention trials PCPT and SELECT.

Ahmed M, Goh C, Saunders E, Cieza-Borrella C, , Kote-Jarai Z, Schumacher FR, Eeles R.

BACKGROUND: The development of prostate cancer can be influenced by genetic and environmental factors. Numerous germline SNPs influence prostate cancer susceptibility. The functional pathways in which these SNPs increase prostate cancer susceptibility are unknown. Finasteride is currently not being used routinely as a chemoprevention agent but the long term outcomes of the PCPT trial are awaited. The outcomes of the SELECT trial have not recommended the use of chemoprevention in preventing prostate cancer. This study investigated whether germline risk SNPs could be used to predict outcomes in the PCPT and SELECT trial.METHODS: Genotyping was performed in European men entered into the PCPT trial (n = 2434) and SELECT (n = 4885). Next generation genotyping was performed using Affymetrix® Eureka™ Genotyping protocols. Logistic regression models were used to test the association of risk scores and the outcomes in the PCPT and SELECT trials.
RESULTS: Of the 100 SNPs, 98 designed successfully and genotyping was validated for samples genotyped on other platforms. A number of SNPs predicted for aggressive disease in both trials. Men with a higher polygenic score are more likely to develop prostate cancer in both trials, but the score did not predict for other outcomes in the trial.
CONCLUSION: Men with a higher polygenic risk score are more likely to develop prostate cancer. There were no interactions of these germline risk SNPs and the chemoprevention agents in the SELECT and PCPT trials.

DOI: https://doi.org/10.1038/s41391-019-0181-y