Genetic mutations associated with sensitivity to neoadjuvant chemotherapy in metastatic colon cancer: A case report and review of literature

Table 1 Summary of evidence for main gene mutations

Genes mutation	Ref.	Total No. of patients	Frequency		Prognosis
			n	%	OS	RFS
KRAS1	Nash et al[19], 2010	188	51	27	Worse
	Teng et al[24], 2012	292	111	38	None
	Karagkounis et al[20], 2013	202	58	29	Worse	Worse
	Lin et al[21], 2014	154	43	28	None
	Margonis et al[22], 2016	512	190	37		None
	Wang et al[23], 2017	300	110	37	Worse
TP53	Tullo et al[25], 1999	40	19	48		Worse
	Yang et al[27], 2001	39	16	41	Better	Better
	Saw et al[26], 2002	60	35	58	None
	De Jong et al[30], 2005	44	16	36	None	None
	Molleví et al[28], 2007	91	46	51	Worse
	Pilat et al[29], 2015	76	42	55	Worse
	Løes et al[33], 2016	164	99	60	None	None
	Frankel et al[31], 2017	165	95	58	None
	Chun et al[32], 2019	401	263	66	None
SMAD4	Mizuno et al[35], 2018	278	37	13	Worse
	Kawaguchi et al[36], 2019	507	56	11	Worse	Worse
APC2	Yamashita et al[34], 2020	396	45	11	Worse	Worse

¹More than 150.

²Represent APC and PIK3CA mutation. OS: Overall survival; RFS: Recurrence-free survival.

Table 2 Summary of evidence for other gene mutations

Genes mutation	Ref.	Summary	Conclusion
CREBBP	Lin et al[37], 2020	TMB-high (> 11 mutations/Mb), male, mutation of RNF43, CREBBP, NOTCH3, PTCH1, CIC, DNMT1 and SPEN were all related to longer OS	CREBBP mutation may be related to higher immunogenicity such as TMB, high expression of mRNA related to immune response, highly infiltrating immune-active cells such as CD8+T cells, active immune-active pathways, and DNA damage repair pathways with an increased number of mutations
	Douglas et al[38],2020	When looking at the complete responder group, mutations were noted in endoscopic biopsy specimens from at least two patients in genes including ARID1A, JAK1, CREBBP, and MTOR (three patients each), that were not seen to be mutated in PR specimens	The authors identified multiple genetic variations in tumor DNA from rectal cancer patients who are poor responders to neoadjuvant chemoradiation, compared to complete responders
POLD1	Hühns et al[40], 2019	The authors performed POLE and POLD1 exonuclease domain Sanger sequencing of 271 unselected colorectal carcinomas and finally identified two microsatellite-stable tumors with somatic POLE p.P286R variants, both with ultrahigh TMBs as demonstrated by whole exome sequencing. In two tumors, a somatic POLE p.V411L and a POLD1 p.E279K, respectively, were found only focally, and TMBs were low. It is commonly assumed that compromise of one allele is sufficient, but this has not been specifically addressed	Taken together, including at least the more common DNA polymerase mutations in NGS panels allows for straightforward identification of hypermutator-type colorectal carcinomas which often may be "immunoreactive". This is important at least in young patients or when a metastasizing stage of disease has been reached and immune-checkpoint therapy enters deliberation
IKZF1	None	No eligible studies	No evidence
PRKCB	None	No eligible studies	No evidence

DNA: Deoxyribonucleic acid; mRNA: Messenger ribonucleic acid; NGS: Next generation sequencing; TMB: Tumor mutation burden.

Table 3 Findings of chemotherapy-related single nucleotide polymorphisms related to a better response

Genes	Detected loci	SNP results	Evidence		Summary
			Drugs	Grades
DPYD	rs3918290	CC (wild-type)	5Fu-based	Level III	For patients with tumor, CC genotype may have a higher drug remission rate than CT genotype. However, there are also studies with inconsistent conclusions
	rs1801159	TT (wild-type)		Level III	For a patient with tumor, TT genotype may have a higher drug remission rate than CT or CC genotype
GSTP1	rs1695	AG (heterozygous mutants)	5Fu + XELOX	Level IIA	For a patient with tumor, AG genotype may have a higher drug remission rate than AA genotype, but comparing with GG genotype, AG genotype may reduce drug remission rate and relate to a poor OS
ERCC2	rs13181	TT (wild-type)	5Fu + Leucovorin + XELOX	Level III	For a patient with CRC, TT genotype may have a lower risk of recurrence and a longer PFS than GG genotype
	rs1052555	GG (wild-type)	Platinum compounds	Level III	For a patient with NSCLC, GG genotype may have a higher drug remission rate than AA or AG genotype
ABCB1	rs1045642	GG (homozygous mutants)		Level III	For a patient with CRC, GG genotype may have a higher drug remission rate than AA or AG genotype
VEGFA	rs25648	CC (wild-type)		Level III	For a patient with gastric cancer, CC genotype may have a higher drug remission rate than CT or TT genotype

CRC: Colorectal cancer; NSCLC: Non-small-cell lung cancer; OS: Overall survival; SNPs: Single nucleotide polymorphisms; XELOX: Oxaliplatin.