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

Published on Apr 10, 2021in Familial Cancer1.76
· DOI :10.1007/S10689-021-00249-X
Inbal Kedar8
Estimated H-index: 8
(Rabin Medical Center),
L Walsh (UW: University of Washington)+ 20 AuthorsYael Goldberg3
Estimated H-index: 3
(TAU: Tel Aviv University)
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.
#1Mev Dominguez-Valentin (Oslo University Hospital)H-Index: 14
#2Julian R. Sampson (Cardiff University)H-Index: 78
Last. Toni T. Seppälä (UH: University of Helsinki)H-Index: 17
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#1Sanne W. ten Broeke (LUMC: Leiden University Medical Center)H-Index: 10
#2Mar Rodríguez-Girondo (LUMC: Leiden University Medical Center)H-Index: 13
Last. Maartje Nielsen (LUMC: Leiden University Medical Center)H-Index: 28
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Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained vi...
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#1Pål Møller (Oslo University Hospital)H-Index: 55
#2Toni T. Seppälä (HYKS: Helsinki University Central Hospital)H-Index: 17
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Background Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. Objective and design This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. Results 3119 patients were followed for a t...
224 CitationsSource
#1Genebo Timotewos (AAU: Addis Ababa University)H-Index: 2
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Abstract Background The Addis Ababa City Cancer Registry, established in September 2011, is the only population-based cancer registry in Ethiopia, covering a catchment population of just over three million habitants. Herein, we report incidence data based on the first two years of registration, 2012–2013. Methods Newly-diagnosed cancer cases in the capital city were actively collected from 22 hospitals, clinics, and diagnostic facilities. Results During 2012–2013, a total of 4139 newly diagnosed...
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#1Jenny von Salomé (Karolinska University Hospital)H-Index: 4
#2Philip S. Boonstra (UM: University of Michigan)H-Index: 12
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Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an ...
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#1Brian H. Shirts (UW: University of Washington)H-Index: 27
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Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories. For 1,462 sequential patients referred for testing by BROCA or ColoSeq multig...
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#1Giovanni Ponti (University of Modena and Reggio Emilia)H-Index: 24
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Founder mutations in specific populations are common in several Mendelian disorders. They are shared by apparently unrelated families that inherited them from a common ancestor that existed hundreds to thousands of years ago. They have been proven to impact in molecular diagnostics strategies in specific populations, where they can be assessed as the first screening step and, if positive, avoid further expensive gene scanning. In Lynch syndrome (LS), a dominantly inherited colorectal cancer dise...
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#1Faraz Bishehsari (NU: Northwestern University)H-Index: 21
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Colorectal cancer (CRC) is one of the leading causes of cancer and cancer-related mortality worldwide. The disease has been traditionally a major health problem in industrial countries, however the CRC rates are increasing in the developing countries that are undergoing economic growth. Several environmental risk factors, mainly changes in diet and life style, have been suggested to underlie the rise of CRC in these populations. Diet and lifestyle impinge on nuclear receptors, on the intestinal ...
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#1Bente A. Talseth-Palmer (University of Newcastle)H-Index: 14
#2Juul T. Wijnen (LEI: Leiden University)H-Index: 71
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The report by Aldred Scott Warthin in 1913 of a cancer family history and expanded on by Henry T. Lynch demonstrated one of the most enduring traits observed in patients with Lynch syndrome. The recognition of a variety of malignancies occurring at differing ages within a single family suggested the role of genetic variance on disease expression in an autosomal dominantly inherited genetic condition. With the identification of the genetic basis of Lynch syndrome and the subsequent collection of ...
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#1Leticia Moreira (University of Barcelona)H-Index: 22
#2Francesc Balaguer (University of Barcelona)H-Index: 44
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Context Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. Objective To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. De...
325 CitationsSource
Cited By1
#1Ido Laish (TAU: Tel Aviv University)H-Index: 7
#2Yael Goldberg (Rabin Medical Center)H-Index: 17
Last. Gili Levi-Reznick (Rambam Health Care Campus)
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Abstract null null Background null Routine screening for establishing Lynch syndrome (LS) in young individuals diagnosed with adenomas is not recommended due to its low yield, and limited sensitivity of the employment of immunohistochemistry for DNA mismatch-repair proteins on polyps. Hence we aimed to evaluate the yield of germline mutational analysis in diagnosis of LS in a young Israeli cohort with colorectal adenomatous polyps. null null null Methods null Data were retrospectively collected ...