bims-lifras 2021-04-11 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒04‒11
nine papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation.
A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer.
Impact of national guidelines on use of BRCA1/2 germline testing, risk management advice given to women with pathogenic BRCA1/2 variants and uptake of advice.
A rare germline CDKN2A variant (47T>G; p16-L16R) predisposes carriers to pancreatic cancer by reducing cell cycle inhibition.
Long-term yield of pancreatic cancer surveillance in high-risk individuals.
Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility.
Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China.
Cutaneous squamous cell carcinoma is associated with Lynch syndrome; widening the spectrum of Lynch syndrome associated tumours.
Insertion of an SVA Element in MSH2 as a Novel Cause of Lynch Syndrome.

BMC Cancer. 2021 Apr 07. 21(1): 363

Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation.

Vidal AF, Ferraz RS, El-Husny A, Silva CS, Vinasco-Sandoval T, Magalhães L, Raiol-Moraes M, Barra WF, Pereira CLBL, de Assumpção PP, de Brito LM, Vialle RA, Santos S, Ribeiro-Dos-Santos Â, Ribeiro-Dos-Santos AM.

  BACKGROUND: Next generation sequencing (NGS) has been a handy tool in clinical practice, mainly due to its efficiency and cost-effectiveness. It has been widely used in genetic diagnosis of several inherited diseases, and, in clinical oncology, it may enhance the discovery of new susceptibility genes and enable individualized care of cancer patients. In this context, we explored a pan-cancer panel in the investigation of germline variants in Brazilian patients presenting clinical criteria for hereditary cancer syndromes or familial history.METHODS: Seventy-one individuals diagnosed or with familial history of hereditary cancer syndromes were submitted to custom pan-cancer panel including 16 high and moderate penetrance genes previously associated with hereditary cancer syndromes (APC, BRCA1, BRCA2, CDH1, CDKN2A, CHEK2, MSH2, MSH6, MUTYH, PTEN, RB1, RET, TP53, VHL, XPA and XPC). All pathogenic variants were validated by Sanger sequencing.
RESULTS: We identified a total of eight pathogenic variants among 12 of 71 individuals (16.9%). Among the mutation-positive subjects, 50% were diagnosed with breast cancer and had mutations in BRCA1, CDH1 and MUTYH. Notably, 33.3% were individuals diagnosed with polyposis or who had family cases and harbored pathogenic mutations in APC and MUTYH. The remaining individuals (16.7%) were gastric cancer patients with pathogenic variants in CDH1 and MSH2. Overall, 54 (76.05%) individuals presented at least one variant uncertain significance (VUS), totalizing 81 VUS. Of these, seven were predicted to have disease-causing potential.
CONCLUSION: Overall, analysis of all these genes in NGS-panel allowed the identification not only of pathogenic variants related to hereditary cancer syndromes but also of some VUS that need further clinical and molecular investigations. The results obtained in this study had a significant impact on patients and their relatives since it allowed genetic counselling and personalized management decisions.

Keywords:  Hereditary cancer; Next generation sequencing; Pan-cancer panel; Pathogenic variant

DOI:  https://doi.org/10.1186/s12885-021-08089-9
Fam Cancer. 2021 Apr 10.

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer.

Kedar I, Walsh L, Levi GR, Lieberman S, Shtaya AA, Nathan SN, Lagovsky I, Tomashov-Matar R, Goldenberg M, Basel-Salmon L, Katz L, Aleme O, Peretz TY, Hubert A, Rothstein D, Castellvi-Bel S, Walsh T, King MC, Pritchard CC, Levi Z, Half E, Laish I, Goldberg Y.

  Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

Keywords:  Anticipation; Deletion; Founder mutation; Lynch syndrome; MSH2

DOI:  https://doi.org/10.1007/s10689-021-00249-x
Hered Cancer Clin Pract. 2021 Apr 09. 19(1): 24

Impact of national guidelines on use of BRCA1/2 germline testing, risk management advice given to women with pathogenic BRCA1/2 variants and uptake of advice.

Meiser B, Kaur R, Morrow A, Peate M, Wong WKT, McPike E, Cops E, Nichols C, Austin R, Fine M, Thrupp L, Ward R, Macrae F, Hiller JE, Trainer AH, Mitchell G, .

  BACKGROUND: This nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients.METHODS: Clinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate.
RESULTS: There were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively (χ = 0.25, p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30-50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women.
CONCLUSIONS: Guidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care.

Keywords:  BRCA1 and BRCA2; Cancer risk; Compliance; Genetic testing; Guidelines

DOI:  https://doi.org/10.1186/s13053-021-00180-3
J Biol Chem. 2021 Apr 03. pii: S0021-9258(21)00420-8. [Epub ahead of print] 100634

A rare germline CDKN2A variant (47T>G; p16-L16R) predisposes carriers to pancreatic cancer by reducing cell cycle inhibition.

Horn IP, Marks DL, Koenig AN, Hogenson TL, Almada LL, Goldstein LE, Romecin Duran PA, Vera R, Vrabel AM, Cui G, Rabe KG, Bamlet WR, Mer G, Sicotte H, Zhang C, Li H, Petersen GM, Fernandez-Zapico ME.

  Germline mutations in CDKN2A, encoding the tumor suppressor p16, are responsible for a large proportion of familial melanoma cases, and also increase risk of pancreatic cancer. We identified four families through pancreatic cancer probands that were affected by both cancers. These families bore a germline missense variant of CDKN2A (47T>G), encoding a p16-L16R mutant protein associated with high cancer occurrence. Here, we investigated the biological significance of this variant. When transfected into p16-null pancreatic cancer cells, p16-L16R was expressed at lower levels than wild type (WT) p16. In addition, p16-L16R was unable to bind CDK4 or CDK6 compared to WT p16, as shown by coimmunoprecipitation assays ,and also was impaired in its ability to inhibit the cell cycle, as demonstrated by flow cytometry analyses. In silico molecular modeling predicted that the L16R mutation prevents normal protein folding, consistent with the observed reduction in expression/stability and diminished function of this mutant protein. We isolated normal dermal fibroblasts from members of the families expressing WT or L16R proteins to investigate the impact of endogenous p16-L16R mutant protein on cell growth. In culture, p16-L16R fibroblasts grew at a faster rate, and most survived until later passages than p16-WT fibroblasts. Further, Western blotting demonstrated that p16 protein was detected at lower levels in p16-L16R than in p16-WT fibroblasts. Together, these results suggest that the presence of a are CDKN2A (47T>G) mutant allele contributes to an increased risk of pancreatic cancer as a result of reduced p16 protein levels and diminished p16 tumor suppressor function.

Keywords:  CDK4; cancer biology; cell cycle; cell proliferation; fibroblast; genetic disease; inherited mutation; melanoma; pancreatic adenocarcinoma

DOI:  https://doi.org/10.1016/j.jbc.2021.100634
Gut. 2021 Apr 05. pii: gutjnl-2020-323611. [Epub ahead of print]

Long-term yield of pancreatic cancer surveillance in high-risk individuals.

Overbeek KA, Levink IJM, Koopmann BDM, Harinck F, Konings ICAW, Ausems MGEM, Wagner A, Fockens P, van Eijck CH, Groot Koerkamp B, Busch ORC, Besselink MG, Bastiaansen BAJ, van Driel LMJW, Erler NS, Vleggaar FP, Poley JW, Cahen DL, van Hooft JE, Bruno MJ, .

  OBJECTIVE: We aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DESIGN: From 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.
RESULTS: 366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1-32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).
CONCLUSION: The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

Keywords:  endoscopic ultrasonography; family cancer; magnetic resonance imaging; pancreatic cancer; surveillance

DOI:  https://doi.org/10.1136/gutjnl-2020-323611
Endocrine. 2021 Apr 05.

Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility.

Mio C, Verrienti A, Pecce V, Sponziello M, Damante G.

  BACKGROUND: Understanding the molecular mechanisms underlying papillary thyroid cancer (PTC) proved to be vital not only for diagnostic purposes but also for tailored treatments. Despite the strong evidence of heritability, only a small subset of alterations has been implicated in PTC pathogenesis. To this reason, we used targeted next-generation sequencing (NGS) to identify candidate variants implicated in PTC pathogenesis, progression, and invasiveness.METHODS: A total of 42 primary PTC tissues were investigated using a targeted next-generation sequencing (NGS) panel enlisting 47 genes involved in DNA repair and tumor progression.
RESULTS: We identified 57 point mutations in 78.5% of samples (n = 32). Thirty-two somatic mutations were identified exclusively in known thyroid cancer genes (BRAF, KRAS, NRAS, and TERT). Unpredictably, 45% of the all identified mutations (n = 25) resulted to be germline, most affecting DNA repair genes. Interestingly, none of the latter variants was in the main population databases. Following ACMG classification, 20% of pathogenic/likely pathogenic and 68% of variant of unknown significance were identified.
CONCLUSIONS: Overall, our results support the hypothesis that rare germline variants in DNA repair genes are accountable for PTC susceptibility. More data, including the segregation analysis in affected families, should be collected before definitely annotate these alterations and to establish their potential prognostic and treatment implications.

Keywords:  DNA repair; Germline variants; Next-generation sequencing; Papillary thyroid cancer

DOI:  https://doi.org/10.1007/s12020-021-02705-1
BMC Cancer. 2021 Apr 07. 21(1): 369

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China.

Qi XP, Zhao JQ, Fang XD, Lian BJ, Li F, Wang HH, Cao ZL, Zheng WH, Cao J, Chen Y.

  BACKGROUND: Germline RET mutations and variants are involved in development of multiple endocrine neoplasia type 2 (MEN2). The present study investigated a spectrum of RET variants, analyzed genotype-phenotype relationships, and evaluated their effect on the MEN2 phenotype in Han Chinese patients.METHODS: Targeted sequencing detected germline RET variants in 697 individuals, including 245 MEN2, 120 sporadic medullary thyroid cancer (MTC), and 15 pheochromocytoma (PHEO) patients and their 493 relatives. In silico analyses and classifications following ACMG-2015 were performed. Demographic, clinical variant types, and endocrine neoplasia molecular diagnosis records were also analyzed.
RESULTS: Nineteen different RET mutations (18 point and 1 del/ins mutations) in 214 patients with MEN2A (97.7%) or MEN2B (2.3%) were found, of which exon 11/10 mutations accounted for 79% (169/214). Nineteen compound mutations were found in 31 patients with MEN2A. Twenty-three variants (18 single and 5 double base substitution/compound variants) non-classification were also found. Of these, 17 (3 of pathogenic, 10 of uncertain significance, 2 of likely benign and 2 as benign) were found in 31 patients with MTC/PHEO. The remaining 6 variants (4 of uncertain significance and 2 of likely benign) found in 8 carriers had no evidence of MEN2. The entire cohort showed MEN2A-related PHEO, all occurring in exons 11/10, particularly at C634. Kaplan-Meier curves showed age-dependent penetration rates of MTC and PHEO, and occurrence rates of PHEO in patients with exon 11 mutations were all higher than those within exon 10; these bilateral PHEO were always associated with exon 11 mutations (all P < 0.05). While patient offspring had PHEO, parents with MEN2A had none, the frequency was approximately 10%. Interestingly, at least 6.8% of families were adoptive. Also, 3 non-hotspot RET variants (R114H, T278N, and D489N) appeared with high frequency. Conversely, polymorphism S836S was absent.
CONCLUSIONS: These data are largely consistent with current evidence-based recommendations in the clinical practice guidelines. Diversity of RET variants or carriers may involve a different natural disease course. Further large-scale targeted sequencing studies will serve as an accurate and cost-effective approach to investigating MEN2 genotype-phenotype correlations for discovery of rare or unknown variants of RET.

Keywords:  Genetic variants; Hyperparathyroidism; Medullary thyroid cancer; Multiple endocrine neoplasia type 2; Pheochromocytoma; RET proto-oncogene

DOI:  https://doi.org/10.1186/s12885-021-08116-9
Br J Dermatol. 2021 Apr 07.

Cutaneous squamous cell carcinoma is associated with Lynch syndrome; widening the spectrum of Lynch syndrome associated tumours.

Ykema BLM, Adan F, Crijns MB, Bleeker FE, Dekker E, Bekkenk MW, Snaebjornsson P, van Leerdam ME.

Dear Editor, Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. Individuals with LS have an increased risk of developing colorectal and many other tumours including skin tumours.1 Sebaceous neoplasms and keratoacanthomas are skin tumours associated with LS, also known as Muir-Torre syndrome. For cutaneous squamous cell carcinoma (SCC), an association with LS has been suggested.

DOI: https://doi.org/10.1111/bjd.20139
Genes Chromosomes Cancer. 2021 Apr 06.

Insertion of an SVA Element in MSH2 as a Novel Cause of Lynch Syndrome.

Yang C, Li Y, Trottier M, Farrell MP, Rai VK, Salo-Mullen E, Gallagher DJ, Stadler ZK, van der Klift HM, Zhang L.

  Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). In this study, we identified and characterized a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and a very strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members. MSK-IMPACT next-generation sequencing and long-range PCR analyses revealed an insertion in MSH2 exon 12 at the c.1972 position in an antisense orientation. The insertion was further characterized as an SVA element approximately 3 kb in length, belonging to the SVA_F1 family of retrotransposons. This variant also segregated with LS related cancers in four affected family members in this family. Based on this evidence, this MSH2 SVA insertion is considered pathogenic. This article is protected by copyright. All rights reserved.

Keywords:  Germline; Lynch Syndrome; MSH2; SVA

DOI:  https://doi.org/10.1002/gcc.22950