Molecular pathology (COR)

Question 1

Esophageal cancer , SCC

Answer 1

Few recurrent alterations

• TP53
• MLL2
• Chromati remodeling gene –> SMARCA4 (stratification of pts -> prognosis)
• FGFR related to VEGF
• PI3K
• EGFR

2 groups

Question 2

Esophageal cancer, ADC

Answer 2

Many recurrent alterations

• TP53
• p16
• PI3K -> hotspot driver mutation
• ELMO1 -> stratification of pts, no therapeutic target
• EGFR (cetuximab -> HER1 inhibitor)

Question 3

GEJ tumors

Answer 3

• TP53 (70%): most common, not targetable
• HER2 (25%): mostly amplification. HER2 status together with MSI!!! HIgh MSI -> no response to trastuzumab
• EGFR, KRAS

4 families

Question 4

Gastric cancer

Answer 4

Patients are hyperstatified based on the molecular landscape. Various combination of alteration (mostly somatic) within a single tumor.

• TP53
• BRA2
• Cell adhesion protein alteration e.g. CDH1
• ARID1A (chromatin-remodeling gene)
• Cellular growth
• MSI instability
• Chromosomal instability (HER2, PTEN)
• Epigenetic alterations

Lauren classification: intestinal classic ADC, diffuse type (CDH1)

4 families

• EBV and MSI analysis
• TMB -> genomically stable or instable

EBV infection
H Pylori

Question 5

CRC

Answer 5

MMR is one of the driver
- MSI analysis -> if high, BRAF (V600E) mutation

Families

• MSI
• KRAS
• TP53

MMR system analysis

Question 6

Pancreatic cancer

Answer 6

Important to identify the immunogenic type that responds to immunotherapy

Question 7

Breast cancer

Answer 7

• ER, PgR, HER2, Ki67
• PIK3CA and TP53 > prognostic groups- Highly recurrent mutations.
• Identification of special histological subtypes
• Evaluate need for CT: 4 prognostic multigene tests -> risk of tumor progression -> division in high risk (need CT) and low risk
• Alterations in gene related to DNA damage response (PARP1, BRCA1, BRCA2) + regulatory genes + MMR system genes. CO occurence, mutual exclusivity, OLAPARIB
• Immunologically cold tumors, immunotherapy targets TILs
• Male BC

Question 8

Endometrial carcinoma

Answer 8

• POLE ultramutated tumors (PTEN, PIK3R1, PIK3CA, TP53)
• MSI hypermutated tumors (PTEN, KRAS, MLH1 methylation, lynch syndrome-related), morphologic appearance
• Low CNVs (CTNNB1, PIK3CA, PTEN)
• High CNVs (serous-like, TP53)

Question 9

Epithelial ovarian cancer

Answer 9

• One of the cancers with highest CNVs

- Recurrent mutations: TP53; BRCA1 and BRCA2 in inherited cases -> PARP1 inhibitors