bims-lifras 2020-02-02 papers

bims-lifras

Biomed News

on Li-Fraumeni Syndrome

Issue of 2020‒02‒02
fifteen papers selected by
Joanna Zawacka-Pankau

Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline.
The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases.
Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy.
The emerging landscape of germline variants in urothelial carcinoma: Implications for genetic testing.
Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.
Surgery in reference centers improves survival of sarcoma patients: a nationwide study.
Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients.
Complete histopathologic examination of risk reduction gastrectomy specimens for CDH1 germline mutation: Is it warranted in routine clinical practice?
Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma.
Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome.
High risk of breast cancer in women with biallelic pathogenic variants in CHEK2.
In search of genetic factors predisposing to familial hairy cell leukemia (HCL): exome-sequencing of four multiplex HCL pedigrees.
The clinical heterogeneity of RUNX1 associated familial platelet disorder with predisposition to myeloid malignancy - A case series and review of the literature.
Familial Pancreatic Cancer at Elderly Siblings in Japan.
Misdiagnosis of High-grade Serous Ovarian Cancer With BRCA Mutation as Endometriotic Cyst Due to Its Unique Gross Morphology: A Case Report and Literature Review.

J Clin Oncol. 2020 Jan 27. JCO1902960

Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline.

Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, Kohn EC, Levine DA, Liu JF, Lu KH, Sparacio D, Annunziata CM.

PURPOSE: To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus.METHODS: A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence.
RESULTS: The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs.
RECOMMENDATIONS: All women diagnosed with epithelial ovarian cancer should have germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in BRCA1/2 genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.

DOI: https://doi.org/10.1200/JCO.19.02960
Cancers (Basel). 2020 Jan 26. pii: E292. [Epub ahead of print]12(2):

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases.

Figlioli G, Kvist A, Tham E, Soukupova J, Kleiblova P, Muranen TA, Andrieu N, Azzollini J, Balmaña J, Barroso A, Benítez J, Bertelsen B, Blanco A, Bonanni B, Borg Å, Brunet J, Calistri D, Calvello M, Chvojka S, Cortesi L, Darder E, Valle JD, Diez O, Consortium E, Eon-Marchais S, Fostira F, Gensini F, Houdayer C, Janatova M, Kiiski JI, Konstantopoulou I, Kubelka-Sabit K, Lázaro C, Lesueur F, Manoukian S, Marcinkute R, Mickys U, Moncoutier V, Myszka A, Nguyen-Dumont T, Nielsen FC, Norvilas R, Olah E, Osorio A, Papi L, Peissel B, Peixoto A, Plaseska-Karanfilska D, Pócza T, Rossing M, Rudaitis V, Santamariña M, Santos C, Smichkoska S, Southey MC, Stoppa-Lyonnet D, Teixeira M, Törngren T, Toss A, Urioste M, Vega A, Vlckova Z, Yannoukakos D, Zampiga V, Kleibl Z, Radice P, Nevanlinna H, Ehrencrona H, Janavicius R, Peterlongo P.

  Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

Keywords:  FANCM truncating variants; PTVs; breast cancer predisposition; breast cancer risk factors; mutation spectrum

DOI:  https://doi.org/10.3390/cancers12020292
BMC Vet Res. 2020 Jan 31. 16(1): 30

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy.

Thumser-Henner P, Nytko KJ, Rohrer Bley C.

  Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in intact female dogs. Their high prevalence in certain breeds suggests a genetic component, as it is the case in human familial breast cancer, distinctly in BRCA2-associated cancers. However, the molecular genetics of BRCA2 in the pathogenesis of canine cancer are still under investigation.Genetic variations of canine BRCA2 comprised single nucleotide polymorphisms, insertions and deletions. The BRCA2 level has been shown to be reduced in tumor gland samples, suggesting that low expression of BRCA2 is contributing to mammary tumor development in dogs. Additionally, specific variations of the BRCA2 gene affect RAD51 binding strength, critically damage the BRCA2-RAD51 binding and further provoke a defective repair. In humans, preclinical and clinical data revealed a synthetic lethality interaction between BRCA2 mutations and PARP inhibition. PARP inhibitors are successfully used to increase chemo- and radiotherapy sensitivity, although they are also associated with numerous side effects and acquired resistance. Cancer treatment of canine patients could benefit from increased chemo- and radiosensitivity, as their cancer therapy protocols usually include only low doses of drugs or radiation. Early investigations show tolerability of iniparib in dogs. PARP inhibitors also imply higher therapy costs and consequently are less likely to be accepted by pet owners.We summarized the current evidence of canine BRCA2 gene alterations and their association with mammary tumors. Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice.

Keywords:  BRCA2; Canine mammary cancer; PARP inhibitors; RAD51

DOI:  https://doi.org/10.1186/s12917-020-2247-4
Cancer Treat Res Commun. 2020 Jan 07. pii: S2468-2942(20)30002-2. [Epub ahead of print]23 100165

The emerging landscape of germline variants in urothelial carcinoma: Implications for genetic testing.

Vlachostergios PJ, Faltas BM, Carlo MI, Nassar AH, Alaiwi SA, Sonpavde G.

  Urothelial carcinoma (UC) of the bladder and upper tract (ureter, renal pelvis) is one of the most frequently occurring malignancies. While the majority of UC are chemically induced by smoking, accumulating evidence from genetic studies have demonstrated a small, but consistent impact of heritable gene variants and family history of UC on the development of the disease. Beyond the established association between upper tract UC and germline mismatch DNA repair defects as a defining feature of Lynch syndrome, newer investigations focusing on moderate- and high-risk cancer-related gene variants in DNA damage repair and other signaling pathways are expanding our knowledge on the heritable genetic basis of UC, opening new avenues in the breadth of genetic testing and in clinical counseling of these patients. Overcoming existing challenges in the interpretation of uncertain findings and family cascade testing may help expand our testing approach and guidelines. Following the paradigm of other tumor types, such as breast and ovarian cancers, germline genetic testing, particularly when combined with somatic testing, has the potential to directly benefit affected UC patients and their families in the future through therapeutic targeting (i.e. with poly(ADP-ribose)) polymerase inhibitors, immune checkpoint inhibitors) and genetically informed screening/surveillance, respectively.

Keywords:  Bladder cancer; Genetic testing; Germline variants; Lynch syndrome; Urothelial carcinoma

DOI:  https://doi.org/10.1016/j.ctarc.2020.100165
Ann Oncol. 2019 Jul;pii: S0923-7534(19)31238-4. [Epub ahead of print]30(7): 1071-1079

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

Nones K, Johnson J, Newell F, Patch AM, Thorne H, Kazakoff SH, de Luca XM, Parsons MT, Ferguson K, Reid LE, McCart Reed AE, Srihari S, Lakis V, Davidson AL, Mukhopadhyay P, Holmes O, Xu Q, Wood S, Leonard C, , , , Beesley J, Harris JM, Barnes D, Degasperi A, Ragan MA, Spurdle AB, Khanna KK, Lakhani SR, Pearson JV, Nik-Zainal S, Chenevix-Trench G, Waddell N, Simpson PT.

  BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer.PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n=26) or BRCA2 (n=22) or from non-carriers (non-BRCA1/2; n=30).
RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2.
CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Keywords:  BRCA1; BRCA2; familial breast cancers; mutation signatures; whole-genome sequencing

DOI:  https://doi.org/10.1093/annonc/mdz132
Ann Oncol. 2019 Jul;pii: S0923-7534(19)31232-3. [Epub ahead of print]30(7): 1143-1153

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

Blay JY, Honoré C, Stoeckle E, Meeus P, Jafari M, Gouin F, Anract P, Ferron G, Rochwerger A, Ropars M, Carrere S, Marchal F, Sirveaux F, Di Marco A, Le Nail LR, Guiramand J, Vaz G, Machiavello JC, Marco O, Causeret S, Gimbergues P, Fiorenza F, Chaigneau L, Guillemin F, Guilloit JM, Dujardin F, Spano JP, Ruzic JC, Michot A, Soibinet P, Bompas E, Chevreau C, Duffaud F, Rios M, Perrin C, Firmin N, Bertucci F, Le Pechoux C, Le Loarer F, Collard O, Karanian-Philippe M, Brahmi M, Dufresne A, Dupré A, Ducimetière F, Giraud A, Pérol D, Toulmonde M, Ray-Coquard I, Italiano A, Le Cesne A, Penel N, Bonvalot S, .

  BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry.PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N=35784) and in the subgroup of incident patient population (N=29497).
RESULTS: Among the 35784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29497 incident patients, 25851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P<0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS].
CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

Keywords:  reference center; relapse; resection; sarcoma; surgery; survival

DOI:  https://doi.org/10.1093/annonc/mdz124
Fam Cancer. 2020 Jan 29.

Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients.

Brand RE, Dudley B, Karloski E, Das R, Fuhrer K, Pai RK, Pai RK.

  The hallmark of Lynch syndrome (LS)-associated neoplasia is DNA mismatch repair protein (MMR) deficiency. Recent studies have demonstrated that histologically normal colonic crypts in patients with LS can exhibit deficient MMR expression. The aim of this study was to determine the feasibility of detecting MMR deficient crypts in random colonoscopic biopsies of normal mucosa in patients with and without LS. Forty-nine patients, including 33 with LS, 12 without LS, and 4 with germline MMR gene variants of uncertain significance (VUS), were prospectively and blindly evaluated by immunohistochemistry for MMR deficient crypts within random normal-appearing mucosal biopsies obtained during surveillance colonoscopy. MMR deficient crypts were identified in 70% (23/33) of patients with LS and in no patients without LS (0/12) (p < 0.001). MMR deficient crypts were identified with nearly equal frequency in both LS patients with and without a cancer history and were associated with germline variants in all four MMR genes and EPCAM. MMR deficient crypts were also identified in LS patients with a history of non-colorectal cancer types, including patients with endometrial cancer, skin sebaceous neoplasms, and renal cancer. Two of the four patients with germline MMR gene VUS had MMR deficient crypts. In conclusion, MMR deficient crypts are a specific biomarker of LS and can be identified in random normal mucosal biopsies in LS patients. Evaluation for MMR deficient crypts in colonoscopic biopsies of normal mucosa can help identify LS patients.

Keywords:  Colonoscopy; Colorectal carcinoma; DNA mismatch repair protein; Immunohistochemistry; Lynch syndrome; MSI

DOI:  https://doi.org/10.1007/s10689-020-00161-w
Ann Diagn Pathol. 2020 Jan 20. pii: S1092-9134(20)30014-9. [Epub ahead of print]45 151473

Complete histopathologic examination of risk reduction gastrectomy specimens for CDH1 germline mutation: Is it warranted in routine clinical practice?

Zhang Q, Yang Z, Karamchandani DM.

  AIMS: CDH1 germline mutation is associated with high penetrance of hereditary diffuse gastric cancer (HDGC). Due to the lack of endoscopically identifiable lesions, routine surveillance is ineffective in the early detection of gastric cancer, and risk-reduction gastrectomy is often recommended. Many academic pathology departments elect to submit the entire gastrectomy specimen for histological examination, which is associated with significantly increased cost, technical and professional time, and turnaround time.METHODS: We present our experience with 5 completely submitted and 2 representatively submitted prophylactic total gastrectomy cases in HDGC patients.
RESULTS: Multifocal intramucosal signet ring cell carcinoma was identified in all cases except one, in which only in situ carcinoma was identified. The tumoral foci (2 to 35 per case; average 14.4) were concentrated in proximal stomach. No submucosal invasion or nodal metastases was seen in any case. The final stage was either stage 0 (pTisN0cM0) or stage 1a (pT1aN0cM0).
CONCLUSIONS: Our findings are in line with that reported in the literature. Considering that deeply invasive carcinoma is very rare in this situation, and no further treatment is indicated for the vast majority of those patients, complete submission and pathologic examination of the entire stomach provides little additional value for routine clinical management. We propose a two-step approach with targeted submission of the proximal stomach, and subsequent entire submission of the remaining stomach if no intramucosal carcinoma is identified during the initial targeted examination.

Keywords:  CDH1 gene; Cadherins; Hereditary neoplastic syndromes; Stomach neoplasms

DOI:  https://doi.org/10.1016/j.anndiagpath.2020.151473
J Med Genet. 2020 Jan 29. pii: jmedgenet-2019-106519. [Epub ahead of print]

Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma.

Buffet A, Calsina B, Flores S, Giraud S, Lenglet M, Romanet P, Deflorenne E, Aller J, Bourdeau I, Bressac-de Paillerets B, Calatayud M, Dehais C, De Mones Del Pujol E, Elenkova A, Herman P, Kamenický P, Lejeune S, Sadoul JL, Barlier A, Richard S, Favier J, Burnichon N, Gardie B, Dahia PL, Robledo M, Gimenez-Roqueplo AP.

  BACKGROUNDS: The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.METHODS: We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum ('Single VHL tumour' cohort), 70 patients with multiple tumours of the VHL spectrum ('Multiple VHL tumours' cohort), 76 patients with a VHL disease as described in the literature ('VHL-like' cohort) and 946 patients with a PPGL were screened for E1' genetic variants.
RESULTS: Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum.
CONCLUSIONS: VHL E1' cryptic exon mutations contribute to 1.32% (1/76) of 'VHL-like' cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.

Keywords:  cryptic exon; paraganglioma; von Hippel-Lindau

DOI:  https://doi.org/10.1136/jmedgenet-2019-106519
J Med Genet. 2020 Jan 28. pii: jmedgenet-2019-106256. [Epub ahead of print]

Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome.

Wang Q, Leclerc J, Bougeard G, Olschwang S, Vasseur S, Cassinari K, Boidin D, Lefol C, Naïbo P, Frébourg T, Buisine MP, Baert-Desurmont S, .

  BACKGROUND: Heterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.METHODS: We report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.
RESULTS: Genomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.
CONCLUSION: Our results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

Keywords:  Lynch syndrome; MMR deficiency; PMS2; cancer predisposition; germline variant

DOI:  https://doi.org/10.1136/jmedgenet-2019-106256
Breast Cancer Res Treat. 2020 Jan 28.

High risk of breast cancer in women with biallelic pathogenic variants in CHEK2.

Rainville I, Hatcher S, Rosenthal E, Larson K, Bernhisel R, Meek S, Gorringe H, Mundt E, Manley S.

  PURPOSE: Compared to breast cancer risk genes such as BRCA2, ATM, PALB2, and NBN, no defined phenotype is currently associated with biallelic pathogenic variants (PVs) in CHEK2. This study compared the prevalence of breast and other cancers in women with monoallelic and biallelic CHEK2 PVs.METHODS: CHEK2 PV carriers were identified through commercial hereditary cancer panel testing (09/2013-07/2019). We compared cancer histories of 6473 monoallelic carriers to 31 biallelic carriers. Breast cancer risks were estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI).
RESULTS: Breast cancer frequency was higher among biallelic CHEK2 PV carriers (80.6%, 25/31) than monoallelic carriers (41.2%, 2668/6473; p < 0.0001). Biallelic carriers were more likely to be diagnosed at or before age 50 (61.3%, 19/31) and to have a second breast cancer diagnosis (22.6%, 7/31) compared to monoallelic carriers (23.9%, 1548/6473; p < 0.0001 and 8.1%, 523/6473; p = 0.0107, respectively). Proportionally more biallelic carriers also had any cancer diagnosis and > 1 primary diagnosis. Compared to women with no PVs, biallelic PV carriers had a higher risk of developing ductal invasive breast cancer (OR 8.69, 95% CI 3.69-20.47) and ductal carcinoma in situ (OR 4.98, 95% CI 2.00-12.35) than monoallelic carriers (OR 2.02, 95% CI 1.90-2.15 and OR 1.82, 95% CI 1.66-2.00, respectively).
CONCLUSIONS: These data suggest that biallelic CHEK2 PV carriers have a higher risk for breast cancer, are more likely to be diagnosed younger, and to have multiple primary breast cancers compared to monoallelic carriers. Biallelic carriers also appear to have a higher risk of cancer overall. Therefore, more aggressive management may be appropriate for women with biallelic PVs in CHEK2 compared with current recommendations for monoallelic carriers.

Keywords:  Biallelic; Breast cancer; CHEK2; Germline

DOI:  https://doi.org/10.1007/s10549-020-05543-3
Leukemia. 2020 Jan 28.

In search of genetic factors predisposing to familial hairy cell leukemia (HCL): exome-sequencing of four multiplex HCL pedigrees.

Pemov A, Pathak A, Jones SJ, Dewan R, Merberg J, Karra S, Kim J, Arons E, Ravichandran S, Luke BT, Suman S, Yeager M, , Dyer MJS, Lynch HT, Greene MH, Caporaso NE, Kreitman RJ, Goldin LR, Spinelli JJ, Brooks-Wilson A, McMaster ML, Stewart DR.

DOI: https://doi.org/10.1038/s41375-019-0702-7
Res Pract Thromb Haemost. 2020 Jan;4(1): 106-110

The clinical heterogeneity of RUNX1 associated familial platelet disorder with predisposition to myeloid malignancy - A case series and review of the literature.

Tang C, Rabbolini DJ, Morel-Kopp MC, Connor DE, Crispin P, Ward CM, Stevenson WS.

  Germline mutations of runt-related transcription factor-1 (RUNX1) cause familial platelet disorder with predisposition to myeloid malignancy (FPDMM), most commonly associated with thrombocytopenia and propensity to develop myeloid neoplasms. A key clinical question is which patients with a family history of thrombocytopenia should undergo genetic testing for RUNX1 mutations. Typically, molecular diagnosis by genetic sequencing is performed when the clinical phenotype is suggestive of this diagnosis; however, our understanding of the spectrum of associated features suggestive of this diagnosis continues to evolve. Herein, we report a case series of 3 unrelated families with RUNX1-associated FPDMM and clinical phenotypes not typically reported with this condition. These cases expand our understanding of FPDMM and highlight the complexity of transcriptional regulation of hematopoiesis and its potentially diverse phenotypes. We describe our approach to diagnosis and management of these individuals and the importance of long-term surveillance in these cases.

Keywords:  RUNX1; familial platelet disorder; familial platelet disorder with predisposition to myeloid malignancy; hereditary myeloid malignancy; inherited thrombocytopenia

DOI:  https://doi.org/10.1002/rth2.12282
Euroasian J Hepatogastroenterol. 2019 Jan-Jun;9(1):9(1): 52-54

Familial Pancreatic Cancer at Elderly Siblings in Japan.

Kashimoto Y, Onji M, Takeji S, Yamamoto S, Miyake T, Uehara T, Kawasaki K, Murakami T, Miyaike J, Oomoto M, Bando K, Horiike N, Abe M, Kumagi T.

  Two female siblings aged 87 and 90 years were clinically diagnosed as pancreatic cancer by abdominal ultrasonography and abdominal contrast-enhanced CT. Pancreatic cancer of these patients was confirmed during the autopsy. Both patients shared risk factors of pancreatic cancer; old age, diabetes, and passive smoking. Strong family history of pancreatic cancer was found in these two patients as their father and younger brother were also suffering from this cancer. The present study seems to report two eldest cases of familial pancreatic cancer in siblings. How to cite this article: Kashimoto Y, Onji M, et al. Familial Pancreatic Cancer at Elderly Siblings in Japan. Euroasian J Hepatogastroenterol 2019;9(1):52-54.

Keywords:  Cancer risk; Elderly siblings; Familial pancreatic cancer.

DOI:  https://doi.org/10.5005/jp-journals-10018-1296
Int J Gynecol Pathol. 2020 Jan 23.

Misdiagnosis of High-grade Serous Ovarian Cancer With BRCA Mutation as Endometriotic Cyst Due to Its Unique Gross Morphology: A Case Report and Literature Review.

Ma Q, Yuan Y, Wang Y, Shao C, Feng W.

It is believed that high-grade serous ovarian cancer (HGSOC) is a solid or multilocular-solid cancer. Here, we report the case of a 40-yr-old woman with a left ovarian unilocular cyst. Ultrasonography and computed tomographic examination confirmed that the cyst was thin-walled and homogenous in thickness without mural nodules. It was considered to be an endometriotic cyst. Left ovarian cyst excision specimens proved it to be HGSOC after pathologic examination. Therefore, the patient underwent radical surgery for HGSOC. Pathologic examination of radical resection specimens confirmed that the HGSOC was still in FIGO stage IA and no fallopian tube lesion was found. Considering that the patient had a history of breast cancer in both the breasts at a young age, it was hypothesized that the breast cancer susceptibility gene (BRCA) gene may have a germline mutation. Next-generation sequencing confirmed the BRCA1 (c.3770_3771delAG) germline mutation in this patient. Previous studies have reported the special morphological characteristics and growth pattern of HGSOC with BRCA mutation in the advanced stage. Our case demonstrates that HGSOC with the BRCA mutation can also be a unilocular cyst with a thin wall and uniform thickness without a mural nodule, and in the early stage, may have unique gross morphology.

DOI: https://doi.org/10.1097/PGP.0000000000000663