scholarly journals Co-Occurrence of Familial Non-Medullary Thyroid Cancer (FNMTC) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Associated Tumors—A Cohort Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Kshama Aswath ◽  
James Welch ◽  
Sriram Gubbi ◽  
Padmasree Veeraraghavan ◽  
Shirisha Avadhanula ◽  
...  

Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)—MLHL, MSH2, MSH6, PMS2, and EPCAM—is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A855-A855
Author(s):  
Kshama Aswath ◽  
James Welch ◽  
Sriram Gubbi ◽  
Mohammad Al Jundi ◽  
Padmasree Veeraraghavan ◽  
...  

Abstract Background: Lynch syndrome (LS) is an autosomal dominant disease caused by germline mutations in mismatch repair genes (MMR), leading to the early manifestation of tumors characterized by microsatellite instability (MSI) in >3 family members across at least 2 generations. MSI is a rare event in thyroid cancer (TC), occurring in up to 2.5% of sporadic cases. There is limited data on germline MMR variants’ role in familial non-medullary thyroid cancer (FNMTC). The goal of this study was to analyze the potential clinical and molecular association between LS and FNMTC. Material and Methods: We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds with FNMTC. We performed a high-throughput whole exome sequencing (WES) of peripheral-blood DNA samples of 168 participants (54 affected by FNMTC and 140 unaffected). The GATK pipeline was used in variant analysis. The NIH Institutional Review Board approved the study. Results: The study included 383 family members (104 affected, 279 unaffected) aged 43.5 [7-99] years, with 2-9 members per family affected by FNMTC. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1 [0.2-5] cm, multifocal growth in 44%, gross extrathyroidal extension in 11.3%, central neck lymph node metastases in 40.3%, lateral neck lymph node metastases in 12.9% of patients, and no distant metastases. Family history screening revealed one family of Caucasian descent meeting the clinical criteria for FNMTC and LS diagnosis with 5 members affected by FNMTC and 8 individuals by Lynch-like tumors (3 with colorectal cancer/colon polyps, 2 with endometrial or ovarian tumors, 1 with kidney cancer, 1 with keratoacanthoma and 1 with unspecified Lynch-like tumors with detailed pathology report unavailable). We performed whole exome sequencing of 10 members from this family (3 affected and 7 unaffected) and remaining 158 study participants and detected exclusively in this family, a heterozygous missense variant rs373226409, in MSH2 gene c2120G>A (pCys707Tyr) in three adults affected by LS-like manifestations and two unaffected children under the age of 18 with clear segregation across three generations. This variant appears to be relatively rare with a minor allele frequency (MAF) of 0.0006 in Caucasians; however, it is more common in the South Asian population at 0.003 MAF. Immunostaining performed on the TC tumor tissue of one of the affected family members revealed intact nuclear expression of MSH2, suggestive of no major effect of the variant on MSH2 expression. Five out of seven in-silico models predicted the variant to be functionally deleterious. Conclusion: The co-occurrence of LS and FNMTC is a rare event, presenting in 2% (1/43) of families in our cohort. A common genetic association between LS and FNMTC has not been identified, and the MSH2 variant observed in this family is unlikely to be an etiologic factor.


BMC Medicine ◽  
2015 ◽  
Vol 13 (1) ◽  
Author(s):  
Ana Carolina de Carvalho ◽  
Cristovam Scapulatempo-Neto ◽  
Danielle Calheiros Campelo Maia ◽  
Adriane Feijó Evangelista ◽  
Mariana Andozia Morini ◽  
...  

2006 ◽  
Vol 67 (7) ◽  
pp. 1712-1716 ◽  
Author(s):  
Junko NAMBU ◽  
Toshikatsu FUKUDA ◽  
Yoshinori KURODA ◽  
Fumito KURANISHI ◽  
Manabu SHIMOMURA ◽  
...  

2017 ◽  
Vol 158 (30) ◽  
pp. 1182-1187
Author(s):  
Gergely Kóder ◽  
Judit Olasz ◽  
László Tóth ◽  
Hilda Urbancsek ◽  
Csilla András ◽  
...  

Abstract: Introduction: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disease, which shows familial clustering. Aim: We would like to emphasize the importance of monitoring the HNPCC syndrome patients by presenting a case of a proven MMR gene mutation carrier and her family tree encompassing 10 years. Materials and method: To screen a suspected HNPCC Hungarian family member we are taking thorough family histories. If the diagnosis of HNPCC was further supported by immunohistology and the microsatellite status, sequencing of the MMR genes was carried out. Results: A novel mutation in exon 6 of the hMSH2 gene leading to the deletion of two nucleotide pairs [c.969-970delTC] was detected in our patient. During the 10-year follow-up period of our patient new HNPCC-associated tumors have developed in several family members. Conslusion: Close surveillance of the patient and its family members at risk was effective, although it requires compliance from the subjects. Orv Hetil. 2017; 158(30): 1182–1187.


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