Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China

Abstract

Background and Aim Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype–phenotype correlation in mutated patients. Methods Mutation screening of 46 unrelated probands was performed using multigene panels by next‐generation sequencing. Clinical data of the index were used to assess genotype–phenotype correlations. Results Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. Conclusion In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.

The Progress of Colorectal Polyposis Syndrome in Chinese Population

“…Li et al performed genetic testing on 46 unrelated patients with clinically suspected adenomatous polyposis syndrome. 54 Only a panel containing 19 hereditary CRC-related genes was used for next-generation sequencing (NGS), and positive variants were confirmed by Sanger sequencing. Variants were found in 42 cases (91.30%), including 35 cases of APC gene variant (76.09%), 3 cases of MUTYH gene variant (1 biallelic variant and 2 homozygous variant) (6.52%), and 4 cases of simultaneous APC gene and MUTYH gene variant (8.70%).…”

Update on Surgical Management of FAP

“…19 Through multigene panels to screen 46 unrelated probands, the Chinese research found that the onset time of upper gastrointestinal polyp is much earlier in patients with both APC and MUTYH mutations than MUTYH or APC mutation carriers, suggesting APC and MUTYH gene mutation analyses should be simultaneous. 20 In addition, many novel APC mutations are discovered by genomic sequence, such as insertion [c.3992_3993insA; p. Thr1332Asnfs à 10] in exon 16, c.646-1G > T, c.1285delC, c.1350_1352delinsAC, c.230_233delTAGA, and Ex3_16DEl (EX3_16/CDS3_15) from different pedigrees, 21,22 which helps us to deeply understand the pathogenic mechanisms and genotype-phenotype relationships of FAP.…”

Chinese consensus on prevention of colorectal neoplasia (2021, Shanghai)

“…252 A study on the gene mutation profile of Chinese FAP patients showed that the rates of APC and MUTYH gene mutation were 76.09% and 6.52%, respectively; the proportion of mutation of both genes was 8.70%. 253 In Western populations, Y179C…”

“…Allelic mutation of the MUTYH gene or pathogenic mutation in both chains of the MUTYH gene can be used to confirm the diagnosis of MAP. [253][254][255] The testing methods primarily include first-generation sequencing combined with multiplex ligation-dependent probe amplification (MLPA) and combined next-generation high-throughput sequencing of multiple genes. 256 The procedure of genetic screening for adenomatous polyposis syndrome is shown in Figure 2.…”