The genetic and epigenetic landscape of early-onset colorectal cancer

Figures & data

Table 1. Lynch syndrome and early-onset colorectal cancer.

Study, year	Cohort characteristics	Testing performed	MSI results, n (%)	IHC results, n (%)	Germline results, n	Ref.
Liu et al., 1995	Excluded HNPCC ^† , FAP, IBD	4 or 5 MSI markers ‘4 MMR genes’ tested in germline	<35: 18/31 (58) 36–55: 8/46 (17) >55: 11/112 (11)	Not performed	3 MSH2 2 MLH1	[9]
Capozzi et al., 1999	Amsterdam Suspected HNPCC ^‡ EOCRC ^§	6–8 MSI markers MLH1, MSH2 germline	Amsterdam: 8/11 (73) Suspected HNPCC: 4/12 (33) EOCRC: 5/24 (21)	Not performed	MLH1 or MSH2 Amsterdam: 6/9 Suspected HNPCC: 1/10 EOCRC: 2/24	[10]
Gryfe et al., 2000	All <50	5–10 MSI markers	MSI-H: 102/607 (17) MSI-L: 20/607 (3) MSS: 485/607 (80)	Not performed	Not performed	[11]
Naidoo et al., 2000	<35 >50	5 MSI markers	<35: MSI-L 6/32 (19); MSI-H 10/32 (31) >50: MSI-L 22/50 (44); MSI-H 6/50 (12)	Not performed	Not performed	[12]
Fernebro et al., 2002	Rectal cancer <50	6 MSI markers MLH1, MSH2 MMR IHC	MSI-H 3/30 (10)	3/30 (10) absent MSH2 0/30 (0) absent MLH1	Not performed	[13]
Losi et al., 2005	<45	MSI MLH1, MSH2 MMR IHC	MSI-H: 14/71 (20)	6/14 (43) absent MLH1 or MSH2	Not performed	[14]
Goel et al., 2010	<50	5 MSI markers MLH1, MSH2, MSH6, PMS2 MMR IHC	MSI-H: 13/75 (17) MSI-L: 3/75 (4) MSS: 59/75 (79)	16/75 (21) absent MMR	Not performed	[15]
Giraldez et al., 2010	≤50 36 with FDR or SDR CRC 8 meeting Amsterdam II	5 MSI markers MLH1, MSH2, MSH6, PMS2 MMR IHC Germline testing based on IHC	MSI-H: 15/140 (11)	20/140 (14) absent MMR	4 MLH1 1 MSH2 6 MSH6 4 biallelic MUTYH	[16]
Chang et al., 2012	<40	5 MSI markers MLH1, MSH2, MSH6, PMS2 MMR IHC	MSI-H: 4/13 (31) MSS: 1/13 (8)	5/75 (7) absent MLH1/PMS2 5/75 (7) absent MSH6 2/75 (3) absent MSH2/MSH6 1/75 (1) absent PMS2	Not performed	[17]

† HNPCC defined as patients meeting Amsterdam Criteria (three affected members in the family, two consecutive generations, one diagnosis under age 50).

‡ Those with suspected HNPCC, but not meeting Amsterdam criteria.

§ Those with no family history of CRC.

EOCRC: Early-onset colorectal cancer; FAP: Familial adenomatous polyposis; FDR: First-degree relative; HNPCC: Hereditary nonpolyposis colorectal cancer; IBD: Inflammatory bowel disease; IHC: Immunohistochemistry; MMR: Mismatch repair; MSI: Microsatellite instability; MSI-H: Microsatellite instability-high; MSI-L: Microsatellite instability-low; MSS: Microsatellite stable; SDR: Second-degree relative.

Table 2.  Germline variants in early-onset colorectal cancer.

Study	Cohort	MSI-H and or absent MMR n patients (%)	Genes tested	Pathogenic or likely pathogenic variants Overall n patients (%) Germline variants found (n)	Variants of uncertain significance	Ref.
Limburg et al. 1997–2002 Multi-center US, Canada, Australia	<50: n = 195 mean age 43	18/155 (11.6) ^†	MLH1, MSH2, MSH6	11/195 (5.6) MLH1 (3), MSH2 (6), MSH6 (2)	14 (7.2)	[21]
Mork et al. 2009–2013 Single-center US	<35: n = 193 Mean age 29	45/173 (26.0) ^†	Phenotype driven	44/193 (22.8) APC (13), biallelic MUTYH (2), CMMRD (2), TP53 (1), monoallelic MUTYH (1), MLH1 (6), MSH2 (5), MSH6 (2), PMS2 (1), EPCAM (1)	6 (3.1)	[22]
Yurgelun et al. 2008–2014 Single-center US	<50: n = 336 Median age 56	70/572 (12.2) ^‡	25-gene panel	52 mutations in 47 patients/336 (14.0) MLH1 (13), MSH2 (4), MSH6 (3), PMS2 (2), APC (3), BRCA1 (2), BRCA2 (4), APC I1307K (4), biallelic MUTYH (3), monoallelic MUTYH (6), BRIP1 (1), ATM (6), CHEK2 (1)	479/1260 (38.0) ^§	[23]
Pearlman et al. 2013–2016 Multi-center US	<50: n = 450 Mean age 43	MSI-H: 49 (10.8) MMR deficient: 48 (10.7)	25-gene panel	75 variants in 72 patients/450 (16.0) MLH1 (13), MSH2 (17), MSH6 (2), PMS2 (6), APC (6), APC I1307K (4), biallelic MUTYH (4), monoallelic MUTYH (8), SMAD4 (1), BRCA1 (2), BRCA2 (4), ATM (4), CHEK2 (1), PALB2 (2), CDKN2A (1)	145 (32.2) ^¶	[24]
Stoffel et al. 1998–2015 Single-center US	<50: n = 430 Mean age 40	MSI-H: 41/202 (20.3)	124 or 67 gene panel	79/315 (25.1) MSH2 (25), MLH1 (24), MSH6 (5), PMS2 (2), APC (10), MUTYH (8), SMAD4 (2), BRCA1 (1), TP53 (1), CHEK2 (1)	21/315 (6.7)	[25]
Toh et al. 2014–2016 Single-center Singapore	<50: n = 88 Mean age 41	MMR deficient: 0/69 (0) ^#	64-gene panel, excluding MMR genes	12/88 (13.6) APC (4), monoallelic MUTYH (2), ATM (1), BRCA2 (1), NTHL1 (1), PALB2 (1), WRN (2)	236/88 ^¶	[26]

† Only reported MMR.

‡ Reported as MSI-H and/or MMR.

§ Includes total cohort of patients (data on only <50 cohort not available).

¶ Some patients had more than one variant.

# Excluded patients with MMR-deficient tumors.

CMMRD: Constitutional mismatch repair deficiency; MMR: Mismatch repair; MSI-H: Microsatellite instability-high; US: United States.

Figure 1. Germline variants (n) by age and penetrance.

(A) Colorectal variants from [24]. (B) Noncolorectal variants from [24]. (C) Colorectal variants from [23]. (D) Noncolorectal variants from [23]. High-penetrance colorectal genes included MLH1, MSH2, MSH6, PMS2, APC, biallelic MUTYH, SMAD4. Moderate-penetrance colorectal genes included APC I1307K, monoallelic MUTYH. High-penetrance noncolorectal genes included BRCA1, BRCA2, CDKN2A, PALB2, TP53. Moderate penetrance noncolorectal genes included ATM, CHEK2, BARD1, BRIP1, NBN.

The Y-axis represents number of patients with a variant. Some patients had more than one variant; the higher-penetrance variant is represented.

Figure 2. LINE-1 hypomethylation in subsets of colorectal cancer.

(A) Significant hypomethylation is seen in both cohorts of patients with EOCRC, from Argentina and Spain, compared with methylation in the normal colon, cohorts of older-onset CRC (one with MSI and the other without MSI, or MSS), and tumors from patients with Lynch syndrome [54]. (B) Patient survival in CRCs with LINE-1 hypomethylation (lower line) was significantly worse than in those patients who do not have this epigenetic alteration (upper line) [54].

EOCRC: Early-onset colorectal cancer; MSI: Microsatellite instability; MSS: Microsatellite stability.

LiuB, FarringtonSM, PetersenGMet al.Genetic instability occurs in the majority of young patients with colorectal cancer. Nat. Med.1(4), 348–352 (1995).

 PubMed Web of Science ®Google Scholar

CapozziE, DellaPuppa L, FornasarigM, PedroniM, BoiocchiM, VielA. Evaluation of the replication error phenotype in relation to molecular and clinicopathological features in hereditary and early onset colorectal cancer. Euro. J. Cancer35(2), 289–295 (1999).

 PubMed Web of Science ®Google Scholar

GryfeR, KimH, HsiehETet al.Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N. Engl. J. Med.342(2), 69–77 (2000).

 PubMed Web of Science ®Google Scholar

NaidooR, TarinM, ChettyR. A comparative microsatellite analysis of colorectal cancer in patients <35 years and >50 years of age. Am. J. Gastroenterol.95(11), 3266–3275 (2000).

 PubMed Web of Science ®Google Scholar

FernebroE, HalvarssonB, BaldetorpB, NilbertM. Predominance of CIN versus MSI in the development of rectal cancer at young age. BMC Cancer2, 25 (2002).

 PubMed Web of Science ®Google Scholar

LosiL, DiGregorio C, PedroniMet al.Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes. Am. J. Gastroenterol.100(10), 2280–2287 (2005).

 PubMed Web of Science ®Google Scholar

GoelA, NagasakaT, SpiegelJ, MeyerR, LichliterWE, BolandCR. Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin. Gastroenterol. Hepatol.8(11), 966–971 (2010).

 PubMed Web of Science ®Google Scholar

GiraldezMD, BalaguerF, BujandaLet al.MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. Clin. Cancer Res.16(22), 5402–5413 (2010).

 PubMed Web of Science ®Google Scholar

ChangDT, PaiRK, RybickiLAet al.Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod. Pathol.25(8), 1128–1139 (2012).

 PubMed Web of Science ®Google Scholar

LimburgPJ, HarmsenWS, ChenHHet al.Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer. Clin. Gastroenterol. Hepatol.9(6), 497–502 (2011).

 PubMed Web of Science ®Google Scholar

MorkME, YouYN, YingJet al.High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer. L. Clin. Oncol.33(31), 3544–3549 (2015).

 PubMed Web of Science ®Google Scholar

YurgelunMB, KulkeMH, FuchsCSet al.Cancer susceptibility gene mutations in individuals with colorectal cancer. J. Clin. Oncol.35(10), 1086–1095 (2017).

 PubMed Web of Science ®Google Scholar

PearlmanR, FrankelWL, SwansonBet al.Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol.3(4), 464–471 (2017).

 PubMed Web of Science ®Google Scholar

StoffelE.M, KoeppeE, EverettJet al.Germline Genetic Features of Young Individuals with Colorectal Cancer. Gastroenterology154(4), 897–905 (2018).

 PubMed Web of Science ®Google Scholar

TohMR, ChiangJB, ChongSTet al.Germline pathogenic variants in homologous recombination and DNA repair genes in an Asian cohort of young-onset colorectal cancer. JNCI Cancer Spectr.2(4), pky054 (2018).

 PubMedGoogle Scholar

AnteloM, BalaguerF, ShiaJet al.A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLoS ONE7(9), e45357 (2012).

 PubMed Web of Science ®Google Scholar