bims-lifras 2021-03-14 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–03–14
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Genomic and Clinical Correlates of Adrenocortical Carcinoma in an Adult Patient with Li-Fraumeni Syndrome: A Case Report.
Endometrial Cancer Risk in Women with Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.
Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review.
BRCA mutation rate and characteristics of prostate tumor in breast and ovarian cancer families: analysis of 6,591 Italian pedigrees.
Rhabdoid Tumor Predisposition Syndrome: From Clinical Suspicion to General Management.
A pathogenic variant in CHEK2 shows a founder effect in Portuguese Roma patients with thyroid cancer.
Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve.
New progress in the study of germline susceptibility genes of myeloid neoplasms.
A modified screening strategy for Lynch syndrome among MLH1-deficient CRCs: Analysis from consecutive Chinese patients in a single center.
Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies.
Age of diagnosis in familial Barrett's associated neoplasia.
A pediatric case of osteosarcoma and tuberous sclerosis complex with a novel germline mutation in the TSC2 gene and a somatic mutation in the TP53 gene.
Defining the Extracellular Matrix of Rhabdomyosarcoma.
Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer.

Curr Oncol. 2020 Dec 31. 28(1): 226-232

Genomic and Clinical Correlates of Adrenocortical Carcinoma in an Adult Patient with Li-Fraumeni Syndrome: A Case Report.

Suraya Bondy, Camilla Tajzler, Sebastien J Hotte, Anil Kapoor, Kevin Zbuk, Aly-Khan A Lalani.

  Li-Fraumeni Syndrome (LFS) is defined by germline mutations of the p53 tumour suppressor gene. Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that is commonly associated with LFS. Most LFS-linked ACC cases occur in children, and limited research has been dedicated to the clinical outcomes and genomics of adult cases with LFS-linked ACC. We report on a 34-year-old female who was diagnosed with three separate malignancies: stage III invasive ductal carcinoma of the right breast, metastatic ACC from the right adrenal gland, and grade 2 pleomorphic sarcoma of the left hand. Her invasive breast ductal carcinoma was treated with neoadjuvant chemotherapy, and she received a bilateral mastectomy after her LFS was confirmed with genetic blood testing. Adrenal ACC was initially treated with a right nephrectomy and adrenalectomy, followed by adjuvant mitotane and two lines of chemotherapy after disease recurrence. Her hand sarcoma was treated by second ray amputation. Further, we conducted deep next-generation sequencing of each of her unique tumour tissue samples using FoundationONE CDx. A whole-genome shot capture followed by in vitro sequencing performed by the Illumina® HiSeq platform revealed a germline P191fs*18 TP53 mutation across all three tissue samples. This case provides insight into the genomics and clinical characteristics of LFS-linked adult-onset ACC and demonstrated that p53 mutations were preserved throughout each malignancy, without apparent treatment pressures on genomic profiling. This case reinforces the critical importance of adopting best practices for LFS, which include the implementation of highly vigilant screening and management of care in a multidisciplinary setting.

Keywords:  Li-Fraumeni Syndrome; adrenocortical carcinoma; next-generation sequencing

DOI:  https://doi.org/10.3390/curroncol28010025
J Natl Cancer Inst. 2021 Mar 12. pii: djab036. [Epub ahead of print]

Endometrial Cancer Risk in Women with Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.

HEBON group

   BACKGROUND: Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain, therefore we assessed this in a large Dutch nationwide cohort study.
METHODS: 5,980 BRCA1/2 (3,788 BRCA1, 2,151 gBRCA2, 41 both BRCA1/BRCA2) and 8,451 non-BRCA1/2 mutation carriers were selected from the HEBON-cohort. Follow-up started at date of nationwide PALGA coverage (January 1, 1989) or at the age of 25 years (whichever came last), and ended at date of EC diagnosis, last follow-up or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared to: 1) general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were two-sided.
RESULTS: Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119,296 and 160,841 person-years, respectively (SIR = 2.83, 95% confidence interval (CI) = 2.18-3.65; and HR = 2.37, 95% CI = 1.53-3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61-4.72; HR = 2.91, 95% CI = 1.83-4.66), serous-like EC (SIR: 12.64, 95% CI = 7.62-20.96; HR = 10.48, 95% CI = 2.95-37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80-3.83; HR = 2.01, 95% CI = 1.18-3.45) and TP53-mutated EC (HR = 15.71, 95% CI = 4.62-53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01-2.87), and serous-like EC risks (SIR = 5.11, 95% CI = 1.92-13.63) were increased when compared to the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%).
CONCLUSIONS: BRCA1/2 mutation carriers have a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.

Keywords:   BRCA1 ; BRCA2 ; HEBON; endometrial cancer; germline; uterine cancer

DOI:  https://doi.org/10.1093/jnci/djab036
Neurosurgery. 2021 Mar 08. pii: nyab019. [Epub ahead of print]

Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review.

Saber Tadros, Aleksei Kondrashov, Sriya Namagiri, Ashis Chowdhury, Yeshavanth Kumar Banasavadi-Siddegowda, Abhik Ray-Chaudhury.

  Hereditary cancer predisposition syndromes (HCS) become more recognizable as the knowledge about them expands, and genetic testing becomes more affordable. In this review, we discussed the known HCS that predispose to central and peripheral nervous system tumors. Different genetic phenomena were highlighted, and the important cellular biological alterations were summarized. Genetic mosaicism and germline mutations are features of HCS, and recently, they were described in normal population and as modifiers for the genetic landscape of sporadic tumors. Description of the tumors arising in these conditions was augmented by representative cases explaining the main pathological findings. Clinical spectrum of the syndromes and diagnostic criteria were tabled to outline their role in defining these disorders. Interestingly, precision medicine has found its way to help these groups of patients by offering targeted preventive measures. Understanding the signaling pathway alteration of mammalian target of rapamycin (mTOR) in tuberous sclerosis helped introducing mTOR inhibitors as a prophylactic treatment in these patients. More research to define the germline genetic alterations and resulting cellular signaling perturbations is needed for effective risk-reducing interventions beyond prophylactic surgeries.

Keywords:  ATM; Germline; Hereditary; MEN1; Mosaicism; NF1; NF2; Neurofibromatosis; P53; PTEN; RB1; VHL; mTOR

DOI:  https://doi.org/10.1093/neuros/nyab019
Cancer Biol Med. 2021 Mar 12. pii: j.issn.2095-3941.2020.0481. [Epub ahead of print]

BRCA mutation rate and characteristics of prostate tumor in breast and ovarian cancer families: analysis of 6,591 Italian pedigrees.

Laura Cortesi, Federica Domati, Annalisa Guida, Isabella Marchi, Angela Toss, Elena Barbieri, Luigi Marcheselli, Marta Venturelli, Simonetta Piana, Claudia Cirilli, Massimo Federico.

   OBJECTIVE: As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selection criteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associated with breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcome among BRCA1 and BRCA2 carriers.
METHODS: Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovarian cancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. The characteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ2) test and Kaplan-Meier methods, respectively.
RESULTS: Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modena selection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positive for BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis and in the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fell in the prostate cancer cluster region (PCCR) at the 3´ terminal of the 7914 codon.
CONCLUSIONS: It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancer and PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.

Keywords:  BRCA genes; Modena criteria; breast cancer; hereditary cancer; ovarian cancer; prostate cancer

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2020.0481
Front Oncol. 2021 ;11 586288

Rhabdoid Tumor Predisposition Syndrome: From Clinical Suspicion to General Management.

Giada Del Baldo, Roberto Carta, Iside Alessi, Pietro Merli, Emanuele Agolini, Martina Rinelli, Luigi Boccuto, Giuseppe Maria Milano, Annalisa Serra, Andrea Carai, Franco Locatelli, Angela Mastronuzzi.

  Rhabdoid tumors are rare aggressive malignancies in infants and young children with a poor prognosis. The most common anatomic localizations are the central nervous system, the kidneys, and other soft tissues. Rhabdoid tumors share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, members of the SWI/SNF chromatin-remodeling complex. Rhabdoid tumor predisposition syndrome (RTPS) is a condition characterized by a high risk of developing rhabdoid tumors, among other features. RTPS1 is characterized by pathogenic variants in the SMARCB1 gene, while RTPS2 has variants in SMARCA4. Interestingly, germline variants of SMARCB1 and SMARCA4 have been identified also in patients with Coffin-Siris syndrome. Children with RTPS typically present with tumors before 1 year of age and in a high percentage of cases develop synchronous or multifocal tumors with aggressive clinical features. The diagnosis of RTPS should be considered in patients with rhabdoid tumors, especially if they have multiple primary tumors and/or in individuals with a family history. Because germline mutations result in an increased risk of carriers developing rhabdoid tumors, genetic counseling, and surveillance for all family members with this condition is recommended.

Keywords:  atypical teratoid/rhabdoid tumors; cancer predisposition syndromes; cancer risk; cancer surveillance; genetic test; rhabdoid tumors

DOI:  https://doi.org/10.3389/fonc.2021.586288
Endocrine. 2021 Mar 08.

A pathogenic variant in CHEK2 shows a founder effect in Portuguese Roma patients with thyroid cancer.

Carolina Pires, Inês Jorge Marques, Daniela Dias, Ana Saramago, Valeriano Leite, Branca Maria Cavaco.

   PURPOSE: Germline mutations in DNA repair-related genes have been recently reported in cases with familial non-medullary thyroid carcinoma (FNMTC). A Portuguese family from the Roma ethnic group with four members affected with papillary thyroid carcinoma (PTC), and three members with multinodular goiter (MNG) was identified. The aim of this study was to investigate the involvement of DNA repair-related genes in the etiology of FNMTC in this family and in the Roma ethnic group.
METHODS: Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing. Sanger sequencing was used for variant confirmation and screening. Twelve polymorphic markers were genotyped for haplotype analysis in the CHEK2 locus.
RESULTS: A germline pathogenic frameshift variant in the CHEK2 gene [c.596dupA, p.(Tyr199Ter)] was detected in homozygosity in the proband (PTC) and in his brother (MNG), being heterozygous in his mother (PTC), two sisters (PTC), and one nephew (MNG). This variant was absent in 100 general population controls. The screening of the CHEK2 variant was extended to other Roma individuals, being detected in 2/33 Roma patients with thyroid cancer, and in 1/15 Roma controls. Haplotype segregation analysis identified a common ancestral core haplotype (Hcac), covering 10 Mb in the CHEK2 locus, shared by affected CHEK2 variant carriers. Analysis of 62 individuals CHEK2 wild-type indicated that none presented the Hcac haplotype. The estimated age for this variant suggested that it was transmitted by a relatively recent common ancestor.
CONCLUSIONS: We identified a founder CHEK2 pathogenic variant, which is likely to underlie thyroid cancer and other cancer manifestations in the Roma population.

Keywords:  CHEK2; DNA repair; Familial non-medullary thyroid carcinoma (FNMTC); Founder pathogenic variant; Thyroid

DOI:  https://doi.org/10.1007/s12020-021-02660-x
Front Endocrinol (Lausanne). 2021 ;12 635370

Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve.

Antonia Christodoulaki, Annekatrien Boel, Maoxing Tang, Chloë De Roo, Dominic Stoop, Björn Heindryckx.

  Diminished ovarian reserve (DOR) is associated with a reduced quantity and quality of the retrieved oocytes, usually leading to poor reproductive outcomes which remain a great challenge for assisted reproduction technology (ART). Women with DOR often have to seek for oocyte donation, precluding genetically related offspring. Germline nuclear transfer (NT) is a novel technology in ART that involves the transfer of the nuclear genome from an affected oocyte/zygote of the patient to the cytoplast of an enucleated donor oocyte/zygote. Therefore, it offers opportunities for the generation of genetically related embryos. Currently, although NT is clinically applied only in women with serious mitochondrial DNA disorders, this technology has also been proposed to overcome certain forms of female infertility, such as advanced maternal age and embryo developmental arrest. In this review, we are proposing the NT technology as a future treatment option for DOR patients. Strikingly, the application of different NT strategies will result in an increase of the total number of available reconstituted embryos for DOR patients.

Keywords:  diminished ovarian reserve; germline nuclear transfer; oocyte quality; polar body transfer; poor ovarian response; spindle transfer

DOI:  https://doi.org/10.3389/fendo.2021.635370
Oncol Lett. 2021 Apr;21(4): 317

New progress in the study of germline susceptibility genes of myeloid neoplasms.

Lei Bi, Tianyuan Ma, Xu Li, Lai Wei, Zinuo Liu, Bingyue Feng, Baoxia Dong, Xiequn Chen.

  In 2016, the World Health Organization incorporated 'myeloid neoplasms with germline predisposition' into its classification of tumors of hematopoietic and lymphoid tissues, revealing the important role of germline mutations in certain myeloid neoplasms, particularly myelodysplastic syndrome and acute myeloid leukemia. The awareness of germline susceptibility has increased, and some patients with myeloid neoplasms present with a preexisting disorder or organ dysfunction. In such cases, mutations in genes including CCAAT enhancer binding protein α (CEBPA), DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41), RUNX family transcription factor 1 (RUNX1), GATA binding protein 2 (GATA2), Janus kinase 2 (JAK2) and ETS variant transcription factor 6 (ETV6) have been recognized. Moreover, with the application of advanced technologies and reports of more cases, additional germline mutations associated with myeloid neoplasms have been identified and provide insights into the formation, prognosis and therapy of myeloid neoplasms. The present review discusses the well-known CEBPA, DDX41, RUNX1, GATA2, JAK2 and ETV6 germline mutations, and other mutations including those of lymphocyte adapter protein/SH2B adapter protein 3 and duplications of autophagy related 2B, GSK3B interacting protein αnd RB binding protein 6, ubiquitin ligase, that remain to be confirmed or explored. Recommendations for the management of diseases associated with germline mutations are also provided.

Keywords:  acute myeloid leukemia; germline mutations; myeloid dysplastic syndrome; myeloid neoplasms; myoproliferative neoplasms

DOI:  https://doi.org/10.3892/ol.2021.12578
Transl Oncol. 2021 Mar 03. pii: S1936-5233(21)00041-3. [Epub ahead of print]14(5): 101049

A modified screening strategy for Lynch syndrome among MLH1-deficient CRCs: Analysis from consecutive Chinese patients in a single center.

Wenmiao Wang, Jianming Ying, Susheng Shi, Qiurong Ye, Shuangmei Zou, Lin Dong, Ning Lyu.

   BACKGROUND: The low prevalence of the BRAF V600E mutation in colorectal cancers (CRCs) in Chinese populations has stimulated concern about the efficacy of BRAF mutation analysis for Lynch syndrome (LS) screening.
METHODS: In total, 169 of 4104 consecutive CRC patients with absent MLH1 staining were analyzed to compare the utility of the BRAF V600E mutation testing with MLH1 promoter methylation analysis in the Chinese population. Germline genetic testing was performed in patients with wild-type BRAF/methylated MLH1.
RESULTS: Compared with BRAF genotyping, the use of MLH1 methylation testing alone to evaluate patients with MLH1 deficiency reduced referral rates for germline testing by 1.8-fold (82.8% vs. 47.1%). However, 6 patients harboring MLH1 promoter methylation were verified to have LS through germline genetic testing. It is notable that all 6 patients had a family history of CRC in at least 1 first-degree relative (FDR) or second-degree relative (SDR). The combination of MLH1 promoter methylation analysis and a family history of CRC could preclude significantly more patients from germline genetic testing than from BRAF mutation testing alone (45.5% vs. 17.2%, p<0.001) and decrease the number of misdiagnosed LS patients with MLH1 promoter methylation.
CONCLUSION: The combination of a family history of CRC with MLH1 promoter methylation analysis showed better performance than BRAF mutation testing in the selection of patients in the Chinese population for germline genetic testing.

Keywords:  BRAF mutation; Lynch syndrome; MLH1 promoter methylation; colorectal cancer; screening strategy

DOI:  https://doi.org/10.1016/j.tranon.2021.101049
Leukemia. 2021 Mar 10.

Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies.

Melanie Decker, Tim Lammens, Alina Ferster, Miriam Erlacher, Ayami Yoshimi, Charlotte M Niemeyer, Martijn P T Ernst, Marc H G P Raaijmakers, Nicolas Duployez, Andreas Flaum, Doris Steinemann, Brigitte Schlegelberger, Thomas Illig, Tim Ripperger.

DOI: https://doi.org/10.1038/s41375-021-01200-w
Fam Cancer. 2021 Mar 11.

Age of diagnosis in familial Barrett's associated neoplasia.

Benita K Glamour, Omar Alaber, Gino Cioffi, Apoorva K Chandar, Jill Barnholtz-Sloan, Wendy Brock, Gary W Falk, Marcia I Canto, Jean S Wang, Prasad G Iyer, Nicholas J Shaheen, William M Grady, Julian A Abrams, Prashanthi N Thota, Amitabh Chak, Andrew E Blum.

  The identification of hereditary cancer genes for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), may prove critical for the development of novel prevention and treatment strategies. Specifically, efforts for detecting BE and EAC susceptibility genes have focused on families with three or more affected members, since these individuals have an earlier age onset compared to non-familial individuals. Given that the use of BE may overestimate the likelihood of disease heritability, we evaluated the age of diagnosis in kindreds with a restricted definition including only confirmed high-grade dysplasia (HGD) or EAC. The Familial Barrett's Esophagus Consortium database was used to identify individuals with HGD and EAC. These individuals were subsequently split into three kindred groups: non-familial-a single affected family member, duplex-two affected family members, and multiplex-three or more affected family members. Age of cancer diagnosis and other risk factors were compared between individuals in these groups. The study included 441 non-familial, 46 duplex, and 13 multiplex individuals. There was a statistically significant difference for age of diagnosis for individuals in the multiplex families compared to the non-familial and duplex families (56.0 versus 64.3, 63.5; p = 0.049). There was no significant difference between demographic factors and other cancer risk factors between family types. The results of this study support a genetic basis for familial Barrett's associated neoplasia and evaluation of the genetic susceptibility to this disease should continue to focus on families with multiple (three or more) affected members.

Keywords:  Barrett’s associated neoplasia; Barrett’s esophagus; Esophageal adenocarcinoma; Familial Barrett’s esophagus

DOI:  https://doi.org/10.1007/s10689-021-00239-z
Pediatr Blood Cancer. 2021 Mar 10. e28960

A pediatric case of osteosarcoma and tuberous sclerosis complex with a novel germline mutation in the TSC2 gene and a somatic mutation in the TP53 gene.

Kaoru Kuroda, Kunihiko Moriya, Tomohiro Nakano, Ryoko Saito, Daichi Sato, Saori Katayama, Hidetaka Niizuma, Munenori Watanuki, Mitsugu Uematsu, Yoji Sasahara, Shigeo Kure.



Keywords:  TP53; TSC2; mTOR inhibitor; osteosarcoma; tuberous sclerosis complex

DOI:  https://doi.org/10.1002/pbc.28960
Front Oncol. 2021 ;11 601957

Defining the Extracellular Matrix of Rhabdomyosarcoma.

Xiaolei Lian, J Steffan Bond, Narendra Bharathy, Sergei P Boudko, Elena Pokidysheva, Jack F Shern, Melvin Lathara, Takako Sasaki, Teagan Settelmeyer, Megan M Cleary, Ayeza Bajwa, Ganapati Srinivasa, Christopher P Hartley, Hans Peter Bächinger, Atiya Mansoor, Sakir H Gultekin, Noah E Berlow, Charles Keller.

  Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood with a propensity to metastasize. Current treatment for patients with RMS includes conventional systemic chemotherapy, radiation therapy, and surgical resection; nevertheless, little to no improvement in long term survival has been achieved in decades-underlining the need for target discovery and new therapeutic approaches to targeting tumor cells or the tumor microenvironment. To evaluate cross-species sarcoma extracellular matrix production, we have used murine models which feature knowledge of the myogenic cell-of-origin. With focus on the RMS/undifferentiated pleomorphic sarcoma (UPS) continuum, we have constructed tissue microarrays of 48 murine and four human sarcomas to analyze expression of seven different collagens, fibrillins, and collagen-modifying proteins, with cross-correlation to RNA deep sequencing. We have uncovered that RMS produces increased expression of type XVIII collagen alpha 1 (COL18A1), which is clinically associated with decreased long-term survival. We have also identified significantly increased RNA expression of COL4A1, FBN2, PLOD1, and PLOD2 in human RMS relative to normal skeletal muscle. These results complement recent studies investigating whether soft tissue sarcomas utilize collagens, fibrillins, and collagen-modifying enzymes to alter the structural integrity of surrounding host extracellular matrix/collagen quaternary structure resulting in improved ability to improve the ability to invade regionally and metastasize, for which therapeutic targeting is possible.

Keywords:  COL18A1; PLOD1/2; matrix; rhabdomyosarcoma; survival

DOI:  https://doi.org/10.3389/fonc.2021.601957
J Natl Cancer Inst. 2021 Mar 06. pii: djab029. [Epub ahead of print]

Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer.

Cathalijne C B Post, Ellen Stelloo, Vincent T H B M Smit, Dina Ruano, Carli M Tops, Lisa Vermij, Tessa A Rutten, Ina M Jürgenliemk-Schulz, Ludy C H W Lutgens, Jan J Jobsen, Remi A Nout, Emma J Crosbie, Melanie E Powell, Linda Mileshkin, Alexandra Leary, Paul Bessette, Hein Putter, Stephanie M de Boer, Nanda Horeweg, Maartje Nielsen, Tom van Wezel, Tjalling Bosse, Carien L Creutzberg.

BACKGROUND: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction, however the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined PORTEC-1,-2 and -3 trial cohort.
METHODS: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into three groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were two-sided.
RESULTS: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to ≤ 60 or ≤ 70 years would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses. Five-year recurrence-free survival (RFS) was 91.7% (95% confidence interval [CI] = 83.1-100%; hazard ratio [HR] = 0.45, 95%CI =0.16-1.24, p = .12) for LS, 95.5% (95% CI = 90.7-100%; HR = 0.17, 95% CI = 0.05-0.55, p = .003) for 'other' versus 78.6% (95% CI = 73.8-83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95%CI = 0.0-24.7%), 1.5% (95%CI = 0.0-4.3%) and 7.0% (95%CI = 3.0-10.9%) within the LS, 'other' and MLH1-hypermethylated MMRd-EC groups.
CONCLUSION: The LS prevalence in the PORTEC-trial population was 2.8%, and among MMRd-ECs 9.5%. Patients with LS-associated ECs showed a trend towards better RFS and higher risk for second cancers compared to patients with MLH1-hypermethylated MMRd-EC.

DOI: https://doi.org/10.1093/jnci/djab029