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Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center.
Poliani, L; Greco, L; Barile, M; Dal Buono, A; Bianchi, P; Basso, G; Giatti, V; Genuardi, M; Malesci, A; Laghi, L.
Afiliação
  • Poliani L; Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, UO Gastroenterologia ed Endoscopia Digestiva, Milan, Italy.
  • Greco L; Laboratory of Molecular Gastroenterology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
  • Barile M; Hereditary Cancer Genetic Clinic, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
  • Dal Buono A; Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
  • Bianchi P; Medical Analysis Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Italy.
  • Basso G; Genomic Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy.
  • Giatti V; Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
  • Genuardi M; Genomic Unit-Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
  • Malesci A; Università Vita-Salute San Raffaele, Milan, Italy.
  • Laghi L; Laboratory of Molecular Gastroenterology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy. Electronic address: luigiandreagiuseppe.laghi@unipr.it.
ESMO Open ; 7(6): 100607, 2022 12.
Article em En | MEDLINE | ID: mdl-36356413
ABSTRACT

BACKGROUND:

Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation. MATERIALS AND

METHODS:

We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history.

RESULTS:

Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH).

CONCLUSION:

Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Neoplasias Colorretais Hereditárias sem Polipose Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Neoplasias Colorretais Hereditárias sem Polipose Idioma: En Ano de publicação: 2022 Tipo de documento: Article