bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒01‒17
twelve papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. J Med Genet. 2021 Jan 15. pii: jmedgenet-2020-107542. [Epub ahead of print]
    Evans DG, Lalloo F, Ryan NA, Bowers N, Green K, Woodward ER, Clancy T, Bolton J, McVey RJ, Wallace AJ, Newton K, Hill J, McMahon R, Crosbie EJ.
      BACKGROUND: Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million.METHODS: Tumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate.
    RESULTS: In total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%, p<0.0001). Overall, 65/134 (48.5%) patients with MLH1 loss and no MLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss.
    CONCLUSIONS: Reflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.
    Keywords:  genetic predisposition to disease; genetic testing; surgical oncology
    DOI:  https://doi.org/10.1136/jmedgenet-2020-107542
  2. Hered Cancer Clin Pract. 2021 Jan 12. 19(1): 8
    Patel SG, Hampel H, Smith D, Gao D, Cockburn M, Kastrinos F.
      BACKGROUND: 16-25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer.AIM: Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps.
    METHODS: We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range.
    RESULTS: A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance.
    CONCLUSIONS: 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes.
    Keywords:  Adenomas; Colorectal cancer; Colorectal polyps; Genetic testing; Lynch syndrome
    DOI:  https://doi.org/10.1186/s13053-020-00164-9
  3. Cancers (Basel). 2021 Jan 08. pii: E198. [Epub ahead of print]13(2):
    Fountzilas E, Eliades A, Koliou GA, Achilleos A, Loizides C, Tsangaras K, Pectasides D, Sgouros J, Papakostas P, Rallis G, Psyrri A, Papadimitriou C, Oikonomopoulos G, Ferentinos K, Koumarianou A, Zarkavelis G, Dervenis C, Aravantinos G, Bafaloukos D, Kosmidis P, Papaxoinis G, Theochari M, Varthalitis I, Kentepozidis N, Rigakos G, Saridaki Z, Nikolaidi A, Christopoulou A, Fostira F, Samantas E, Kypri E, Ioannides M, Koumbaris G, Fountzilas G, Patsalis PC.
      Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.
    Keywords:  BRCA2; inherited; overall survival; predictive; prognostic
    DOI:  https://doi.org/10.3390/cancers13020198
  4. PLoS One. 2021 ;16(1): e0236907
    Tokunaga H, Iida K, Hozawa A, Ogishima S, Watanabe Y, Shigeta S, Shimada M, Yamaguchi-Kabata Y, Tadaka S, Katsuoka F, Ito S, Kumada K, Hamanaka Y, Fuse N, Kinoshita K, Yamamoto M, Yaegashi N, Yasuda J.
      Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.
    DOI:  https://doi.org/10.1371/journal.pone.0236907
  5. Int J Mol Sci. 2021 Jan 07. pii: E531. [Epub ahead of print]22(2):
    Lindner AK, Schachtner G, Tulchiner G, Thurnher M, Untergasser G, Obrist P, Pipp I, Steinkohl F, Horninger W, Culig Z, Pichler R.
      Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.
    Keywords:  DNA mismatch repair genes; Lynch syndrome; MMR; checkpoint inhibitor; immunotherapy; microsatellite instability; upper urinary tract; urothelial cancer
    DOI:  https://doi.org/10.3390/ijms22020531
  6. Genet Med. 2021 Jan 13.
    Santos M, Lanillos J, Roldan-Romero JM, Caleiras E, Montero-Conde C, Cascón A, Climent MA, Anguera G, Hernando S, Laínez N, Robledo M, Robles L, de Velasco G, García-Donas J, Rodriguez-Antona C.
      PURPOSE: Germline pathogenic variants are estimated to affect 3-5% of renal cell carcinoma (RCC) patients. However, higher mutational prevalence in non-clear cell RCC (non-ccRCC) and advanced disease has been suggested.METHODS: To clarify the prevalence of pathogenic germline variants in metastatic RCC, we sequenced 29 cancer susceptibility genes in 294 unselected metastatic RCC cases plus 21 patients with clinical hereditary features. In 145 tumors, genes frequently mutated in RCC were sequenced and methylation was assessed in selected cases.
    RESULTS: Germline variants in RCC predisposition genes (FH, VHL) were detected in 1.4% of the unselected metastatic patients, with higher frequency in non-ccRCC versus ccRCC (6.4% and 0.4%; P = 0.0025) and in younger patients (P = 0.036). Among the 315 studied patients, 14% of non-type 1 papillary cases (4 of 28), all metastatic <1 year after diagnosis, carried a FH germline variant with loss of heterozygosity and tumor genome hypermethylation. Variants in other cancer-associated genes (e.g., MUTYH, BRCA2, CHEK2) occurred in 5.1% of the unselected series, with unclear significance for RCC.
    CONCLUSION: Our findings confirm a high prevalence of pathogenic germline variants in RCC predisposition genes in metastatic non-ccRCC, and highlight that metastatic patients with papillary type 2 or unconventional histologies compatible with FH would benefit from genetic screening.
    DOI:  https://doi.org/10.1038/s41436-020-01062-0
  7. Cancer Sci. 2021 Jan 09.
    Yoshida R, Hagio T, Kaneyasu T, Gotoh O, Osako T, Tanaka N, Amino S, Yaguchi N, Nakashima E, Kitagawa D, Ueno T, Ohno S, Nakajima T, Nakamura S, Miki Y, Hirota T, Takahashi S, Matsuura M, Noda T, Mori S.
      Genes involved in the homologous recombination repair pathway-as exemplified by BRCA1, BRCA2, PALB2, ATM and CHEK2-are frequently associated with hereditary breast and ovarian cancer syndrome. Germline mutations in the loci of these genes with loss of heterozygosity or additional somatic truncation at the wildtype allele, lead to the development of breast cancers with characteristic clinicopathological features and prominent genomic features of homologous recombination deficiency, otherwise referred to as "BRCAness." Whereas clinical genetic testing for these and other genes has increased the chances of identifying pathogenic variants, there has also been an increase in the prevalence of variants of uncertain significance, which poses a challenge to patient care because of the difficulties associated with making further clinical decisions. To overcome this challenge, we sought to develop a methodology to re-classify the pathogenicity of these unknown variants using statistical modeling of BRCAness. The model was developed with LASSO logistic regression by comparing 116 genomic attributes derived from 37 BRCA1/2 biallelic mutant and 32 homologous recombination-quiescent breast cancer exomes. The model exhibited 95.8% and 86.7% accuracies in the training cohort and the Cancer Genome Atlas validation cohort, respectively. Through application of the model for variant re-classification of homologous recombination-associated hereditary breast and ovarian cancer causal genes and further assessment with clinicopathological features, we finally identified one likely pathogenic and five likely benign variants. As such, the BRCAness model developed from the tumor exome was robust and provided a reasonable basis for variant re-classification.
    Keywords:  BRCAness; Hereditary Breast and Ovarian Cancer Syndrome; Homologous Recombination Deficiency; LASSO logistic regression; Variants of Uncertain Significance
    DOI:  https://doi.org/10.1111/cas.14803
  8. Hered Cancer Clin Pract. 2021 Jan 09. 19(1): 7
    Xie T, Feng Q, Li Z, Lu M, Li J, Lizaso A, Xiang J, Zhang L, Shen L, Peng Z.
      BACKGROUND: Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).CASE PRESENTATION: We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.
    CONCLUSION: Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
    Keywords:  CMMRD; Case report; Heterogeneity; ICI; MSH6
    DOI:  https://doi.org/10.1186/s13053-021-00165-2
  9. JNCI Cancer Spectr. 2021 Feb;5(1): pkaa083
    Kurian AW, Ward KC, Abrahamse P, Hamilton AS, Katz SJ.
      Breast cancer patients increasingly undergo genetic testing. To examine chemotherapy indications for germline pathogenic variant (PV) carriers, we linked results of germline testing to Georgia and California Surveillance, Epidemiology, and End Results registry records, including 21-gene recurrence score (RS) results, for breast cancer patients diagnosed in 2013-2017. All statistical tests were 2-sided. Patients (N=37 349) had RS results of whom 714 had BRCA1, BRCA2, CHEK2, ATM, PALB2, or Lynch syndrome (MLH1, MSH2, MSH6, PMS2) PVs. For women aged 50 years or older at breast cancer diagnosis, RS often exceeded the chemotherapy benefit threshold (≥26) with BRCA1 (71.7% vs 14.4% with none; P <.001), PALB2 (37.1%; P = .001), and BRCA2 (44.3%; P < .001) PVs. Results were similar for women diagnosed at younger than 50 years of age. PVs in BRCA1, but not BRCA2, PALB2, ATM, CHEK2, or Lynch syndrome genes, were associated with elevated RS on multivariable analysis (P < .001). Results may inform RS testing decisions in breast cancer patients with PVs.
    DOI:  https://doi.org/10.1093/jncics/pkaa083
  10. Eur Urol Oncol. 2021 Jan 09. pii: S2588-9311(20)30209-1. [Epub ahead of print]
    Karlsson Q, Brook MN, Dadaev T, Wakerell S, Saunders EJ, Muir K, Neal DE, Giles GG, MacInnis RJ, Thibodeau SN, McDonnell SK, Cannon-Albright L, Teixeira MR, Paulo P, Cardoso M, Huff C, Li D, Yao Y, Scheet P, Permuth JB, Stanford JL, Dai JY, Ostrander EA, Cussenot O, Cancel-Tassin G, Hoegel J, Herkommer K, Schleutker J, Tammela TLJ, Rathinakannan V, Sipeky C, Wiklund F, Grönberg H, Aly M, Isaacs WB, Dickinson JL, FitzGerald LM, Chua MLK, Nguyen-Dumont T, , Schaid DJ, Southey MC, Eeles RA, Kote-Jarai Z.
      BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk.
    DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.
    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.
    RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).
    CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.
    PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
    Keywords:  ATM gene mutations; Genetic predisposition; Prostate cancer; Targeted screening and therapy
    DOI:  https://doi.org/10.1016/j.euo.2020.12.001
  11. Curr Opin Hematol. 2021 Jan 07. Publish Ahead of Print
    Iacobucci I, Mullighan CG.
      PURPOSE OF REVIEW: In the past decade, numerous studies analysing the genome and transcriptome of large cohorts of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients have substantially improved our knowledge of the genetic landscape of these diseases with the identification of heterogeneous constellations of germline and somatic mutations with prognostic and therapeutic relevance. However, inclusion of integrated genetic data into classification schema is still far from a reality. The purpose of this review is to summarize recent insights into the prevalence, pathogenic role, clonal architecture, prognostic impact and therapeutic management of genetic alterations across the spectrum of myeloid malignancies.RECENT FINDINGS: Recent multiomic-studies, including analysis of genetic alterations at the single-cell resolution, have revealed a high heterogeneity of lesions in over 200 recurrently mutated genes affecting disease initiation, clonal evolution and clinical outcome. Artificial intelligence and specifically machine learning approaches have been applied to large cohorts of AML and MDS patients to define in an unbiased manner clinically meaningful disease patterns including, disease classification, prognostication and therapeutic vulnerability, paving the way for future use in clinical practice.
    SUMMARY: Integration of genomic, transcriptomic, epigenomic and clinical data coupled to conventional and machine learning approaches will allow refined leukaemia classification and risk prognostication and will identify novel therapeutic targets for these still high-risk leukaemia subtypes.
    DOI:  https://doi.org/10.1097/MOH.0000000000000629
  12. BMC Cancer. 2021 Jan 09. 21(1): 45
    Xu Y, Li C, Zheng CZ, Zhang YQ, Guo TA, Liu FQ, Xu Y.
      BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. Comparison of prognosis between LS and sporadic CRC (SCRC) were rare, with conflicting results. This study aimed to compare the long-term outcomes between patients with LS and SCRC.METHODS: Between June 2008 and September 2018, a total of 47 patients were diagnosed with LS by genetic testing at Fudan University Shanghai Cancer Center. A 1:2 propensity score matching was performed to obtain homogeneous cohorts from SCRC group. Thereafter, 94 SCRC patients were enrolled as control group. All of enrolled patients received curative surgeries and standardized postoperative monitoring. The long-term survival rates between the two groups were compared, and the prognostic factors were also analyzed.
    RESULTS: The 5-year overall survival rate of LS group was 97.6%, which was significantly higher than of 82.6% for SCRC group (χ2 = 4.745, p = 0.029). The 5-year recurrence free survival rate showed no significant differences between the two groups (78.0% for LS group vs. 70.6% for SCRC patients; χ2 = 1.260, p = 0.262). The 5-year tumor free survival rates in LS group was 62.1% for LS patients, which were significantly lower than of 70.6% for SCRC group (χ2 = 4.258, p = 0.039). Subgroup analysis of recurrent patients show that the LS group had longer overall survival than the SCRC group after combined chemotherapy. By multivariate analysis, we found that tumor recurrence of primary CRC [Risk ratio (95% (confidence interval): 48.917(9.866-242.539); p < 0.001] and late TNM staging [Risk ratio (95% (confidence interval): 2.968(1.478-5.964); p = 0.002] were independent risk factors for OS.
    CONCLUSION: LS patients have better long-term survival prognosis than SCRC patients, even though the two groups have statistically comparable recurrence free survival. Combined chemotherapy is an effective treatment for LS patients who developed primary CRC recurrence. Standardized postoperative monitoring for LS patients may enable detection of metachronous tumors at earlier stages, which was a guarantee of a favorable prognosis despite lower tumor free survival.
    Keywords:  Chemotherapy; Colorectal cancer; Lynch syndrome; Mismatch repair; Survival
    DOI:  https://doi.org/10.1186/s12885-020-07771-8