Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.
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http://dx.doi.org/10.1002/gcc.23231 | DOI Listing |
Zhonghua Wei Chang Wai Ke Za Zhi
December 2024
Int J Mol Sci
November 2024
Department of Molecular Genetics and The National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, Ráth György u. 7-9, 1122 Budapest, Hungary.
Using multigene panel testing for the diagnostic evaluation of patients with hereditary breast and ovarian cancer (HBOC) syndrome often identifies clinically actionable variants in genes with varying levels of penetrance. High-penetrance genes (, , , , , , ) inform specific clinical surveillance and therapeutic decisions, while recommendations for moderate-penetrance genes (, , , , , , , , , , , ) are more limited. A detailed disease history, including pedigree data, helps formulate the most appropriate and personalised management strategies.
View Article and Find Full Text PDFAnn Surg Oncol
December 2024
Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Background: Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare.
View Article and Find Full Text PDFCancers (Basel)
October 2024
Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited.
View Article and Find Full Text PDFBiomedicines
September 2024
UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, and Affiliated Hospitals, Cape Town 7704, South Africa.
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