Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study

Wangefjord, Sakarias; Sundström, Magnus; Zendehrokh, Nooreldin; Lindquist, Kajsa Ericson; Nodin, Björn; Jirström, Karin; Eberhard, Jakob

doi:10.1186/2042-6410-4-17

Cited by 27 publications

(26 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, in the here examined cohort, it has recently been shown that mutation in KRAS codon 13, but not in codon 12, was associated with a significantly reduced cancer specific survival which is in line with other previous publications [16], [38], [39] [40], and most previous studies have not considered the prognostic value of specific mutations [7]–[9], [37], [41]. Furthermore, KRAS codon 13 mutation was found to be significantly associated with metastatic disease, and codon 12 mutation with mucinous tumour type, indicating that specific KRAS mutations have different impact on protein functionality, and hence influence clinical outcome in CRC patients differently [16].…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Associations of Anthropometric Factors with KRAS and BRAF Mutation Status of Primary Colorectal Cancer in Men and Women: A Cohort Study

et al. 2014

Self Cite

View full text Add to dashboard Cite

Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist- and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmö Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRAS-mutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.

show abstract

Section: Discussionsupporting

confidence: 93%

“…BRAF mutations are more frequent in women, in right-sided tumours and are more often associated with lower differentiation grade, mucinous histology and, subsequently, a poor prognosis [9], [11]–[16].…”

Section: Introductionmentioning

confidence: 99%

Associations of Anthropometric Factors with KRAS and BRAF Mutation Status of Primary Colorectal Cancer in Men and Women: A Cohort Study

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…These findings were supported by two additional studies in 2009 and 2012 [255,256]. In contrast, Wangefjord and colleagues found that KRAS codon 13 mutations were associated with significantly reduced cancer specific survival in women, but not in men, although only in unadjusted analyses [257]. We recently confirmed these results on overall survival for women with stage III disease in a large population representative series of CRC (Merok et al, submitted manuscript).…”

Section: Prognostic Biomarkerssupporting

confidence: 65%

Portrait of the PI3K/AKT pathway in colorectal cancer

Danielsen¹,

Eide²,

Nesbakken³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

230

200

View full text Add to dashboard Cite

“…Furthermore, a study of 160 CRCs of varying tumor stages and treatments found that KRAS codon 13, but not codon 12, mutations were associated with higher S-phase fractions, increased nodal metastases, and adverse outcome compared to wild type (16). A Swedish population-based study of 525 CRCs reported that individuals with KRAS codon 13 (but not codon 12) mutations experienced shorter cancer-specific survival in unadjusted, but not adjusted, analysis (30). Limitations of prior studies include the inconsistent incorporation of patients with BRAF mutations (in the comparison group) and variable patient therapies, which can confound the interpretation of the KRAS prognostic data (31-33).…”

Section: Discussionmentioning

confidence: 99%

KRAS Codon 12 and 13 Mutations in Relation to Disease-Free Survival in BRAF–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)

Yoon

Tougeron

Shi

et al. 2014

Clinical Cancer Research

141

View full text Add to dashboard Cite

Purpose We examined the prognostic impact of specific KRAS mutations in stage III colon adenocarcinoma patients receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild type tumors, since BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild type tumors. Because KRAS mutations in codon 12 (n=779) or 13 (n=220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by hazard ratios (HR) using Cox models. Results KRAS mutations in codon 12 (multivariate HR 1.52; 95% confidence interval [CI] 1.28–1.80; P<.0001) or codon 13 (multivariate HR 1.36; 95% CI 1.04–1.77; P=.0248) were significantly associated with shorter DFS compared to patients with wild type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P<.0001), proximal tumor site (P<.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P<.0001). Conclusion KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting.

show abstract

Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study

Cited by 27 publications

References 48 publications

Associations of Anthropometric Factors with KRAS and BRAF Mutation Status of Primary Colorectal Cancer in Men and Women: A Cohort Study

Associations of Anthropometric Factors with KRAS and BRAF Mutation Status of Primary Colorectal Cancer in Men and Women: A Cohort Study

Portrait of the PI3K/AKT pathway in colorectal cancer

KRAS Codon 12 and 13 Mutations in Relation to Disease-Free Survival in BRAF–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)

Contact Info

Product

Resources

About