Biallelic <i>NTHL1</i> Mutations in a Woman with Multiple Primary Tumors

Rivera, Bárbara; Castellsagué, Ester; Bah, Ismaël; Kempen, Léon C van; Foulkes, William D.

doi:10.1056/nejmc1506878

Cited by 77 publications

(58 citation statements)

References 5 publications

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“…82 A subsequent case report of a Canadian woman of German ancestry with early-onset colorectal oligopolyposis and numerous diverse invasive cancer diagnoses identified biallelic NTHL1 mutations. 83 In both reports, somatic genetic analysis of the cancers and adenomas from patients with biallelic NTHL1 mutations demonstrated a relative increase in G:C>T:A transitions, similar to what has been observed in MUTYH -associated polyposis and fitting with the base excision repair defect predicted from loss of normal NTHL1 function. 82,83 …”

Section: Hereditary Colorectal Cancersupporting

confidence: 56%

“…83 In both reports, somatic genetic analysis of the cancers and adenomas from patients with biallelic NTHL1 mutations demonstrated a relative increase in G:C>T:A transitions, similar to what has been observed in MUTYH -associated polyposis and fitting with the base excision repair defect predicted from loss of normal NTHL1 function. 82,83 …”

Section: Hereditary Colorectal Cancersupporting

confidence: 56%

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Advances in Hereditary Colorectal and Pancreatic Cancers

Underhill

Germansky

Yurgelun

2016

Clinical Therapeutics

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Purpose Innovations in genetic medicine have lead to improvements in the early detection, prevention, and treatment of cancer for patients with inherited risks of gastrointestinal cancer, particularly hereditary colorectal cancer and hereditary pancreatic cancer. Methods This review provides an update on recent data and key advances that have improved the identification, understanding, and management of patients with hereditary colorectal cancer and hereditary pancreatic cancer. Findings This review details recent and emerging data that highlight the developing landscape of genetics in hereditary colorectal and pancreatic cancer risk. A summary is provided of the current state-of-the-art practices for identifying, evaluating, and managing patients with suspected hereditary colorectal cancer and pancreatic cancer risk. The impact of next-generation sequencing technologies in the clinical diagnosis of hereditary gastrointestinal cancer and also in discovery efforts of novel genes linked to familial cancer risk are discussed. Emerging targeted therapies that may play a particularly important role in the treatment of patients with hereditary forms of colorectal cancer and pancreatic cancer are also reviewed. Current approaches for pancreatic cancer screening and the psychosocial impact of such procedures are also detailed. Implications Given the availability of novel diagnostic, risk-reducing, and therapeutic strategies that exist for patients with hereditary risk for colorectal or pancreatic cancer, it is imperative that clinicians be vigilant about evaluating patients for hereditary cancer syndromes. Continuing to advance genetics research in hereditary gastrointestinal cancers will allow for more progress to be made in personalized medicine and prevention.

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Section: Hereditary Colorectal Cancersupporting

confidence: 56%

Section: Hereditary Colorectal Cancersupporting

confidence: 56%

Advances in Hereditary Colorectal and Pancreatic Cancers

Underhill

Germansky

Yurgelun

2016

Clinical Therapeutics

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“…3; 7; 10 After causal variants in those genes were initially described in only a few families, identification of additional cases expanded the mutation spectrum and allowed refinement of the respective phenotypes. 8; 9; 52; 53 …”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Adam

Spier

Zhao

et al. 2016

The American Journal of Human Genetics

209

161

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In around 30% of families with colorectal adenomatous polyposis, no germline mutation in the previously-implicated genes APC, MUTYH, POLE, POLD1, or NTHL1 can be identified, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis was performed. We identified two unrelated individuals with differing compound-heterozygous loss-of-function germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1g>a, c.2760delC, c.3001-2a>c) was indicated on RNA and protein level. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST) and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the loss-of-function effect and causal relevance of the mutations. The pedigrees, genotypes, and the frequency of MSH3 mutations in the general population are consistent with an autosomal recessive mode of inheritance. Both index persons had an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study we describe biallelic germline mutations of MSH3 in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

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“…MUTYH -associated polyposis (MAP, MIM 608456) and the recently delineated NTHL1 -associated polyposis (NAP, MIM 616415) are caused by biallelic germline mutations inactivating the base excision repair genes MUTYH [15], and NTHL1 [16, 17], respectively. Adam et al [18] showed in two unrelated families that biallelic truncating mutations in the fifth MMR gene, MSH3, cause a similar polyposis syndrome.…”

Section: Discussionmentioning

confidence: 99%

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency

et al. 2016

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In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in ‘ultramutated’ sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.

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Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors

Cited by 77 publications

References 5 publications

Advances in Hereditary Colorectal and Pancreatic Cancers

Advances in Hereditary Colorectal and Pancreatic Cancers

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency

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